Sec. Neuroendocrine Science
Genotype-Phenotype Relationships and Endocrine Findings in Prader-Willi Syndrome
- Laboratório de Alta Complexidade, Instituto Nacional da Saúde da Mulher, da Criança e Do Adolescente Fernandes Figueira, Fiocruz, Rio de Janeiro, Brazil
Prader-Willi syndrome (PWS) is a complex imprinting disorder related to genomic errors that inactivate paternally-inherited genes on chromosome 15q11-q13 with severe implications on endocrine, cognitive and neurologic systems, metabolism, and behavior. The absence of expression of one or more genes at the PWS critical region contributes to different phenotypes. There are three molecular mechanisms of occurrence: paternal deletion of the 15q11-q13 region; maternal uniparental disomy 15; or imprinting defects. Although there is a clinical diagnostic consensus criteria, DNA methylation status must be confirmed through genetic testing. The endocrine system can be the most affected in PWS, and growth hormone replacement therapy provides improvement in growth, body composition, and behavioral and physical attributes. A key feature of the syndrome is the hypothalamic dysfunction that may be the basis of several endocrine symptoms. Clinical and molecular complexity in PWS enhances the importance of genetic diagnosis in therapeutic definition and genetic counseling. So far, no single gene mutation has been described to contribute to this genetic disorder or related to any exclusive symptoms. Here we proposed to review individually disrupted genes within the PWS critical region and their reported clinical phenotypes related to the syndrome. While genes such as MKRN3, MAGEL2, NDN, or SNORD115 do not address the full spectrum of PWS symptoms and are less likely to have causal implications in PWS major clinical signs, SNORD116 has emerged as a critical, and possibly, a determinant candidate in PWS, in the recent years. Besides that, the understanding of the biology of the PWS SNORD genes is fairly low at the present. These non-coding RNAs exhibit all the hallmarks of RNA methylation guides and can be incorporated into ribonucleoprotein complexes with possible hypothalamic and endocrine functions. Also, DNA conservation between SNORD sequences across placental mammals strongly suggests that they have a functional role as RNA entities on an evolutionary basis. The broad clinical spectrum observed in PWS and the absence of a clear genotype-phenotype specific correlation imply that the numerous genes involved in the syndrome have an additive deleterious effect on different phenotypes when deficiently expressed.
Prader-Willi syndrome (PWS; OMIM 176270) was first described in 1956 by Andrea Prader, Alexis Labhart and Heinrich Willi based on a study of nine children with a common clinical tetrad: short stature, intellectual disability, obesity, and small hands and feet (1, 2). The phenotypic analysis was expanded in the following years and decades, revealing the complexity of the syndrome, affecting endocrine, cognitive and neurologic systems, metabolism, and behavior. PWS was the first human disease to be related to genomic imprinting errors, and also the first one shown to be caused by uniparental disomy (3, 4). This rare genetic disorder has a prevalence of 1 in 10,000–30,000 live births, males and females are affected equally in all ethnic groups (5).
The PWS critical region on chromosome 15q11-q13 is monoallelically expressed by paternally inherited genes, exclusively. The absence of expression of one or more of these genes contributes to different phenotypes of PWS (6, 7) and there are three main mechanisms of occurrence: paternal deletion of the 15q11-q13 region; maternal uniparental disomy 15; or imprinting defects (8–10). On the other hand, in the same region, the loss of expression of the UBE3A gene (preferentially maternally expressed) drives to Angelman syndrome, with completely different clinical characteristics. By their common implicated region and mechanisms, both syndromes are considered sister imprinted disorders (11, 12).
Clinical manifestations vary with age, impacting multiple body systems (Table 1). Fetal size is usually within the normal range. Compared to unaffected siblings, birth weight and body mass index (BMI) are 15% lower on average. Prenatal hypotonia may cause decreased fetal movement, abnormal fetal position at delivery, and increased incidence of assisted delivery or cesarean section (14, 15).
Severe hypotonia is a clinical hallmark of PWS, leading to failure to thrive during infancy due to lethargy and poor suck. Other common neonatal findings are decreased movement and spontaneous arousal, weak cry, thick saliva, and poor reflexes (13, 16). Around 9 months of life, eating behavior starts to normalize, and the hypotonic status tends to improve, but mild-to-moderate hypotonia persists throughout life, with reduced muscle mass and tone (9, 17).
Physical and social milestones (as sitting, walking, first words, and reading) are delayed and can be achieved at about double the normal age (18). Most individuals have mild intellectual disability, learning difficulties, and poor academic performance. During early infancy, characteristic behavioral problems are common, such as stubbornness, manipulation, compulsiveness, self-injury, and difficulty with change in routine (5, 19, 20). Another common feature in the syndrome is sleep disruption, related to sleep apnea that impairs the quality and efficiency of sleep, frequently associated with excessive daytime sleepiness, and sedentary behavior with a higher predisposition to obesity (13, 21).
In later childhood, individuals with PWS will reach severe obesity unless food intake is strictly controlled by family and caretakers. The lack of satiety (hypothalamic origin) results in hyperphagia, with obsessive food seeking. In uncontrolled cases, obesity, and its complications are the major causes of morbidity and mortality: respiratory insufficiency, cardiovascular problems, metabolic syndrome, sleep apnea, and type 2 diabetes mellitus (22, 23). Mortality rates range between 1.25 and 3% per year (24, 25). Hyperphagia in PWS is still not fully understood and controlling appetite remains a challenge.
The endocrine system can be the most affected in PWS. Growth hormone (GH) deficiency is present in up to 74% of cases and is associated with short stature, small hands and feet, low motor strength, increased fat mass, and decreased movement and energy expenditure (26, 27). GH replacement therapy has shown positive effects not only on growth and body composition but also on development, behavior, and nocturnal respiratory abnormalities, although a careful respiratory follow up is mandatory during long-term GH administration (28–34). Hypogonadism affects both sexes and is manifested as hypogenitalism, incomplete pubertal development and infertility in most individuals (35). Hypogonadism is thought to have a hypothalamic origin, and subsequent insufficient secretion of pituitary gonadotropins and sexual hormones (testosterone or estrogen) (7, 36, 37). Other endocrine abnormalities include hypothyroidism (20–30%), central adrenal insufficiency (about 5%) and type 2 diabetes (up to 25%) due to obesity complications (24, 38–41).
Molecular Genetics and Diagnostic
The hypothalamic dysfunction observed in PWS may be the basis of several symptoms (such as hypotonia, developmental delay or obesity) that overlaps features of other conditions on clinical grounds, like normal obesity and intellectual disability (42). Definitive diagnosis requires DNA testing. The PWS region spans ~6 Mb on the long arm of chromosome 15 (Figure 1). Within this region, at least 2.5 Mb comprises genes with differential expression depending on parental origin. This locus holds protein-coding genes and several non-coding RNAs, which are believed to be involved in the regulation of alternative splicing, mainly in the brain (10, 16).
Figure 1. Chromosome map of 15q11.2-q13.1 region. Symbols: ovals, protein-coding genes; rectangles, RNA genes; BP1, breakpoint 1; BP2, breakpoint 2; BP3, breakpoint 3; Type 1, BP1-BP3 deletion with ~6 Mb; Type 2, BP2-BP3 deletion with ~5.3 Mb; Cen, Centromere; Tel, Telomere; IC, Imprinting Center.
The bicistronic gene SNURF-SNRPN is central to the PWS region and crucial to understanding the methylation pattern in the syndrome. The CpG island at the 5′ end of SNURF-SNRPN (encompassing the promoter region, exon 1 and intron 1) is differentially imprinted according to parental origin: the unmethylated paternal allele is expressed while the methylated maternal allele is repressed (43). The PWS imprinting center (PWS-IC, Figure 1) involves the CpG island and exon 1 within the 4.3 Kb smallest region of overlap (44). Furthermore, SNURF-SNRPN expression produces a long transcript also including PWS-IC, Six snoRNA genes, IPW and UBE3A antisense (Figure 1), which is hypothesized to repress paternal UBE3A (45–48).
Most PWS patients (65–75%) present a 5–6 Mb deletion at 15q11-q13 from the paternal origin (16, 49). There are two proximal breakpoints and a common distal breakpoint (Figure 1), these regions are flanked by low copy repeat sequences that predispose to abnormal chromosomal pairing and uneven crossing-over, resulting in errors during meiosis (50, 51). Maternal Uniparental Disomy (mDUP) occurs when both chromosomes 15 are inherited from the mother and accounts for ~20–30% of cases, being associated with advanced maternal age (9, 15). Imprinting defects are caused by epimutations or microdeletions in the PWS-IC in 1–3% of PWS cases. These individuals have biparental allele inheritance, but a maternal-only DNA methylation pattern (11, 52).
Clinical and molecular complexity in PWS enhances the importance of genetic diagnosis in therapeutic definition and genetic counseling. Only DNA methylation analysis can consistently diagnose the syndrome in all three molecular classes (deletion, mUPD, and imprinting defects) and differentiate it from Angelman Syndrome (9, 52). The methylation analysis targets the 5′ CpG island of the SNURF-SNRPN locus and will correctly diagnose more than 99% of cases. Currently, there are three assays with this detection capacity: methylation-specific PCR (MS-PCR, the gold standard), methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and methylation-sensitive high-resolution melting (MS-HRM) (53–58).
After methylation status confirmation, defining the exact molecular mechanism behind the syndrome origin is important for genetic counseling. Sporadic deletion cases have <1% risk of recurrence, while rare cases of structural abnormalities involving chromosome 15 (such as translocations, ring formation, isochromosome or inversions) can be as high as 25–50% and fluorescence in situ hybridization (FISH) can address the deletion source (59–65). mUPD 15 is typically de novo (recurrence <1%), proband and parents should be investigated by small nucleotide polymorphisms (SNP) microarray for accurate counseling (66, 67). Most imprinting defects cases are classified as epimutations with no alteration in the DNA sequence and have <1% recurrence risk. However, 15% of individuals with imprinting defects present a paternally inherited microdeletion (7.5–100 kb) in the PWS-IC, in which cases the risk of recurrence is 50%. IC analysis by MS-MLPA or DNA sequencing will address the exact origin of this event (5, 44).
Genotype-Phenotype Relationships in Prader-Willi Syndrome
None of the PWS genetic errors are associated with exclusive symptoms. However, the most prevalent molecular classes (deletion and mUPD) show statistical differences in frequency or severity in some clinical characteristics. Patients with paternal deletion were more related to feeding problems, sleep disturbances, hypopigmentation and speech and language deficits (68). Individuals with the larger type 1 deletion (Figure 1) have been reported to have better academic performance and intellectual abilities, and more compulsiveness when compared to type 2 deletion patients (69, 70). Several other features are more common in mUPD individuals, such as post-term delivery, higher verbal IQ, psychosis and autism spectrum disorder (15, 69, 71–75). On the other hand, mUPD patients are less likely to have the typical PWS facial appearance or hypopigmentation (16). So far, no single gene mutation has been described to contribute to this genetic disorder. Here we proposed to review genes individually disrupted within the PWS critical region and their reported clinical phenotypes related to the syndrome.
The Makorin Ring Finger Protein 3 (MKRN3, ZNF127) gene encodes a zinc finger protein of the Makorin family and is paternally expressed ubiquitously in human adult tissues, with the highest level in testis, although its exact mechanism of action remains to be elucidated (76). This gene is associated with inhibition of puberty initiation, and loss of function mutations in MKRN3 are recognized as the main genetic cause of Central Precocious Puberty (77). This correlation has been described by distinct studies with different ethnic groups, affecting equally both sexes, with all mutations segregated in a paternal manner at MKRN3 (78–81). Experimental models with mice also support the correlation between mutations in Mkrn3 and puberty dysfunctions, suggesting it may play a role in the hypothalamic-pituitary-gonadal axis (77–79). Altogether, this makes MKRN3 a strong candidate gene for hypogonadism and infertility in PWS.
The physiological consequence of loss of expression of MAGE Family Member L2 (MAGEL2) has been related to phenotypic characteristics of PWS (82). Magel2-null mice exhibited endocrine dysfunction similar to PWS: neonatal growth retardation; excessive weight gain; increased adiposity after weaning; impaired hypothalamic regulation and changes in circadian rhythm (83, 84). Hyperphagia, commonly observed in individuals with PWS, is associated with a defect in the hypothalamic arcuate nucleus, which is the major action site of multiple complex interactions between neuropeptide Y (NPY), agouti-related peptide (AgRP), proopiomelanocortin (POMC), and leptin, regulating the food intake and body weight (85, 86). NPY/AgRP interaction stimulates food intake, whereas POMC reduces it. Loss of MAGEL2 expression disturbs leptin-mediated depolarization of POMC neurons, indicating that food intake is being less repressed and fat storage regulated by leptin is uncontrolled (87, 88). Additionally, loss of expression of Magel2 impairs reproductive function in mice. Magel2-null females showed extended and irregular estrous cycles, while males displayed decreased testosterone levels, and reduced pheromone detection, which has a direct relationship between the main olfactory epithelium and the hypothalamic GnRH neuronal system (89, 90). These results suggest that lack of expression of MAGEL2 contributes to the reproductive deficiencies observed in PWS and also highlights the role of normal circadian rhythm in maintaining fertility.
Therein, specific point mutations on the paternal allele of MAGEL2 were reported in 4 individuals with PWS spectrum phenotype: muscle hypotonia, weight gain, developmental delay, and hypogonadism. Although all clinical characteristics were consistent with PWS clinical diagnosis, methylation analysis on the promoter-exon 1 region of the SNURF-SNRPN gene showed normal allelic patterns (82). All four subjects were diagnosed with an autism spectrum disorder, intellectual disability, and different degrees of clinical and behavioral features of PWS. Although not a main characteristic, autism is present in 19% of individuals with PWS (71). These four individuals presented a normal methylation pattern, not compatible with PWS, despite similar clinical conditions, which was subsequently called Schaaf-Yang Syndrome (SYS) (91). Recent data of an international cohort of 78 patients with truncating MAGEL2 mutations emphasized that SYS overlaps with PWS on clinical grounds in the early stages of life but diverges with the advance of childhood and adolescence (92). PWS features such as hypopigmentation, facial appearance, small hands and feet, thick saliva, behavioral problems are not commonly seen in SYS. And above all distinct symptoms, SYS does not usually cause the high appetite and severe obesity observed in PWS, which can disassociate MAGEL2 and the hyperphagia condition.
The Necdin (NDN) gene encodes a DNA binding protein highly expressed in mature hypothalamic neurons (93). It has been postulated as a key regulator of GnRH levels both in vitro and in vivo, modulating essential intracellular processes for neurite and axonal outgrowth (94–96). Lack of NDN reduces GnRH gene expression, leads to decreased numbers of GnRH neurons, and decreased targeting of GnRH axons to the median eminence of the hypothalamus during development, which can contribute to hypogonadism and infertility in PWS. Also, Necdin paternal-deficient mice were associated with alterations in serotonin and respiratory systems, resulting in irregular breathing and sleep apneas, commonly observed in PWS. Another important evidence reported with Ndn-KO mice was sudden death due to respiratory disorders, which is the main side effect associated with GH therapy (97–99). NDN might be a genetic factor contributing to apneas and respiratory dysfunctions of PWS.
Interestingly, (100) described three patients with atypical deletions related to PWS. Patient 1 was deleted for MKRN3, MAGEL2, and NDN with no PWS major clinical criteria, except for obesity, developmental delay, and high pain threshold. Patients 2 and 3 had a deletion encompassing NPAP1, SNURF-SNRPN, and the SNORD genes, but did not reach MKRN3, MAGEL2, and NDN, and presented PWS major clinical signs (100). This report suggests that a paternal deficiency of MKRN3, MAGEL2, and NDN is not sufficient to generate the full PWS phenotype and postulates NPAP1, SNURF-SNRPN, and the SNORD genes (discussed ahead) to be the critical region for PWS. These results contradict other studies and exemplify the complexity to establish a genotype-phenotype relationship in PWS (78, 82, 83, 98, 99, 101, 102).
The Prader-Willi region encompasses a series of long non-coding RNAs (lncRNAs) which are characteristically more than 200 nucleotides long and can be involved in epigenetic modifications of DNA, and regulation of gene expression at transcriptional and post-transcriptional levels (103–105). The first lncRNA inside the PWS region is the Prader-Willi Region Non-Protein Coding RNA 1 (PWRN1), biallelically expressed in the testis and kidneys, and monoallelic expressed in the brain, in addition to being an alternative 5′ part of SNURF–SNRPN (106). Wawrzik et al. (107) hypothesized that the action of PWRN1 on the imprinting mechanism may be indirect through keeping the paternal allele in an open chromatin configuration, allowing access to transcription factors (107). The main limitation for further confirmation studies is the lack of gene orthology in mice (108–110).
The Nuclear Pore Associated Protein 1 (NPAP1), formerly known as Chromosome 15 Open Reading Frame 2 (C15orf2), is an intronless gene that is biallelically expressed in adult testis and monoallelically expressed in fetal brain, including the hypothalamus which is related to several endocrine features of PWS (106, 111). Moreover, this gene is associated with the Nuclear Pore Complex (NPC), in which the main function is to regulate macromolecular transport between the nucleus and the cytoplasm. NPCs also participates in several nuclear processes, such as gene regulation, mRNA biogenesis, and cell cycle control. Likewise PWRN1, due to the lack of orthology in mice the exact role of the NPAP1 gene in the development of PWS is not clear (112).
The Small Nuclear Ribonucleoprotein Polypeptide N (SNRPN) gene is located within the central region associated with PWS and has an important regulatory role over the imprinted genes located in chromosome 15 (113, 114), while the SNRPN Upstream Reading Frame (SNURF) gene is encoded by an evolutionarily-conserved upstream open reading frame and is localized to the nucleus (115). SNURF-SNRPN is a complex bicistronic gene encoding two different proteins, and the PWS-IC is found at its 5' end. SNURF is encoded by exons 1–3 and produces a small nuclear protein of unknown function (113), exons 4–10 correspond to the SNRPN portion and encode the protein SmN, involved in mRNA splicing (43). It also holds six snoRNA genes located telomerically which are expressed as a long transcript (46). The SmN protein shows the highest expression in the brain and heart (115–117). Despite its central position in PWS, the function and regulation of the many alternative transcripts of SNURF-SNRPN are still poorly understood (48).
Within the long SNURF-SNRPN transcript, there are a series of Small Nucleolar RNAs (snoRNAs) thought to participate in DNA methylation, alternative splicing and post-transcriptional regulation (10, 118). The PWS region encompasses five single copy snoRNA genes (SNORD64, SNORD107, SNORD108, SNORD109A, and SNORD109B) and two snoRNA gene clusters (SNORD115 and SNORD116). The expression of SNORD genes varies in different human and mouse tissues, suggesting specificity in post-transcriptional activity (46, 119–122). Although most of the SNORDs are ubiquitously expressed in human tissues, SNORD115 and SNORD109B appear to be restricted to the brain. Our understanding of the single-copy SNORDs in PWS remains extremely limited, but some progress has been made with the clusters: SNORD116 has 29 tandemly repeats and SNORD115 is composed of 48 gene copies (118). Given that SNORD sequences are well-conserved across placental mammals (especially in primates and rodents), this suggests they have an evolutionary functional role (123, 124).
A minimal critical region has emerged implicating that the SNORD116 cluster is crucial for most of the PWS phenotype, based on clinical evidence on rare patients with small deletions (150–200 Kb) or translocations (11, 125–128). Experimental studies on Snord116-KO mice displayed PWS features such as post-natal growth retardation and hyperphagia (129–132). Remarkably, a Snord116-KO mice model specifically in NPY neurons in the hypothalamic arcuate nucleus summarized the same overall phenotype observed in mice lacking Snord116 globally; low birth weight, increased body weight gain in early adulthood, increased energy expenditure and hyperphagia (130). This suggests an important role of Snord116 in controlling NPY neuronal functions, and thus food intake and energy homeostasis. Also, a recent study reported Snord116-deficient mice with decreased activity of the hypothalamic prohormone convertase PC1 impairing the prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin, pointing to an important part of SNORD116 and PC1 deficiency in the main neuroendocrine features of PWS (133). Interestingly, it was shown that a mouse Snord116 deletion model displayed loss or shift in methylation dynamics in 97% of CpG islands in the cerebral cortex dependent on the circadian cycle. And this disrupted epigenetic rhythm had a strong overlap between mouse and human genes related to meal timing, circadian biology, and obesity (134). In the recent years, SNORD116 has emerged as a critical, and possibly, determinant candidate in PWS not only by its highly conserved sequence in the minimal critical region, but also because paternal deletions affecting the expression of NDN, MKRN3, MAGEL2, or SNORD115 genes do not address the full spectrum of PWS symptoms (10, 100, 123, 135, 136).
The Imprinted in Prader-Willi Syndrome (IPW) gene is a lncRNA known to modulate another evolutionarily distinct imprinted gene cluster at the human chromosomal region 14q32 expressed only from maternally inherited alleles (137). IPW is widely expressed both in fetal and adult tissues, exclusively from the paternal allele (138). It has been postulated that IPW has no biological consequences in PWS, based on the relatively poor conservation between human and mouse sequences (138), and the fact that mice with a paternally inherited deletion including Ipw did not show PWS symptoms (139). However, Stelzer et al. (137) proposed that lack of expression of IPW results in aberrant upregulation of maternally expressed genes at the 14q32 imprinted cluster, pointing that the action of IPW on the imprinting mechanism of this locus occurs by histone modification, and consequently, transcription reduction (137). This hypothesis is supported by clinical reports of affected individuals with mUPD 14 (overexpression of maternal genes) presenting PWS-like phenotypes, such as neonatal hypotonia, small hands and feet, intellectual disability and hyperphagia (140–142). These findings pinpoint a regulatory cross-talk between 15q11-13 and 14q32 imprinted loci, but further, suggest that some PWS phenotypes may arise from different chromosomal regions other than the PWS critical locus (143, 144).
SNORD115 gene is the most characterized SNORD within the PWS region. It presents a complementary sequence of 18 nucleotides with the mRNA encoding the serotonin receptor 5-HT2C, perfectly base pairing with exon V that undergoes both alternative RNA splicing and RNA editing (post-transcriptional changes to specific nucleotide sequences) (118). Mice with a large deletion encompassing the Snord115 cluster developed normally to adulthood with apparently no significant defects (139). And there are also clinical reports on patients with an entire deletion of the SNORD115 gene cluster that did not present any PWS major clinical signs (135, 136). Taken together, these findings suggest that lack of SNORD115 is not sufficient to cause PWS, but a phenotypic effect when absent along with other genes in the PWS critical region cannot be excluded. Actually, the 5-HT2C gene encodes G protein-coupled receptor specific to the brain, whose activation is associated with a variety of physiological processes, such as dopamine modulation, anxiety, sleep regulation, satiety response, energy balance, and locomotor activity (145). Interestingly, experimental studies have described 5-HT2C receptor knockout mice that developed are hyperphagia and late-onset obesity, two major clinical features of PWS in humans (146, 147). Therefore, the absence of SNORD115 expression in PWS accompanied by the possible post-transcriptional impairment of the 5-HT2C receptor activity may be partly responsible for some of the behavioral and metabolic features of the syndrome.
The establishment of a causal genotype-phenotype relationship can bring light to new therapeutic approaches for PWS. Epigenetic therapy has been used in cancer treatment mostly focusing on the identification of small molecules and compounds with the capacity to reverse the epigenetic changes (epigenome reprogramming) (145, 148). The successful experience obtained from the epigenetic-cancer therapies contributes to the development of similar approaches for genomic imprinting disorders. Recent studies have shown that histone methyltransferase inhibitors are capable of reactivating the expression of paternally expressed SNRPN and SNORD116 from the maternal chromosome, both in PWS mouse models and in cultured PWS patient-derived fibroblasts (149, 150). Although further investigation needs to be performed in vivo, epigenetic therapy aiming PWS genes in the maternal chromosome could reverse, or at least regulate, some PWS clinical conditions such as hyperphagia and behavioral problems (151). This data supports future studies to assess translational epigenetic-based therapies for PWS in humans.
PWS is a complex imprinting disorder caused by the lack of expression of paternally-inherited genes on chromosome 15q11-q13 with severe implications on endocrine, cognitive and neurologic systems, metabolism, and behavior. The PWS critical region encompasses five protein-coding genes (MKRN3, MAGEL2, NDN, NPAP1, and SNURF-SNRPN) and more than 80 RNA genes (PWRN1, IPW, and several SNORDs) but their contribution to unique PWS phenotypes is still unclear. The broad clinical spectrum and the absence of a clear genotype-phenotype specific correlation imply that the numerous genes involved in PWS have an additive deleterious effect when deficiently expressed. So far, the lack of expression of the SNORD116 gene cluster has arisen as the best explanation for most of the PWS phenotype, yet there is a clear need to investigate more of its mechanism of action, especially the incorporation into ribonucleoprotein complexes, possibly acting in hypothalamic and endocrine functions in adulthood and perinatal period. Besides SNORD115 and SNORD116, our understanding of the biology of the PWS SNORD genes is still rather shallow. These SNORDs exhibit all the hallmarks of RNA methylation guides and can associate with other proteins to form functional ribonucleoprotein complexes. Also, the SNORD sequences are well-conserved across placental mammals, strongly asserting that they have a functional role as RNA entities under evolutionary pressure. A better understanding about genotype-phenotype in PWS can open space for new therapeutic approaches especially for patients that present side effects related to the current standard treatment, and develop genetic counseling for the different levels of severity in PWS that require specific and constant medical follow-up, improving the life quality of patients, family, and caretakers.
RC, IF, HC, and LGu contributed to the writing of the manuscript. LGo provided consultation and contributed to the writing of the manuscript.
This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ) and was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
2. Butler MG, Meaney FJ, Palmer CG, Opitz JM, Reynolds JF. Clinical and cytogenetic survey of 39 individuals with Prader-Labhart-Willi syndrome. Am J Med Genet. (1986) 23:793–809. doi: 10.1002/ajmg.1320230307
5. Driscoll DJ, Miller JL, Schwartz S, Cassidy SB. Prader-Willi Syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews. Seattle, WA: University of Washington (2017). p. 1–38.
12. Chamberlain SJ, Lalande M. Neurobiology of disease neurodevelopmental disorders involving genomic imprinting at human chromosome 15q11 – q13. Neurobiol Dis. (2010) 39:13–20. doi: 10.1016/j.nbd.2010.03.011
13. Gunay-Aygun M, Schwartz S, Heeger S, O'Riordan MA, Cassidy SB. The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. Pediatrics. (2001) 108:e92–e92. doi: 10.1542/peds.108.5.e92
15. Butler MG, Sturich J, Myers SE, Gold J, Kimonis V, Driscoll DJ. Is gestation in Prader-Willi syndrome affected by the genetic subtype? J Assist Reprod Genet. (2009) 26:461–6. doi: 10.1007/s10815-009-9341-7
18. Whittington J, Holland A, Webb T, Butler J, Clarke D, Boer H. Academic underachievement by people with Prader-Willi syndrome. J Intellect Disabil Res. (2004) 48:188–200. doi: 10.1111/j.1365-2788.2004.00473.x
19. Jauregi J, Arias C, Vegas O, Alén F, Martinez S, Copet P, et al. A neuropsychological assessment of frontal cognitive functions in Prader-Willi syndrome. J Intellect Disabil Res. (2007) 51:350–65. doi: 10.1111/j.1365-2788.2006.00883.x
20. Copet P, Jauregi J, Laurier V, Ehlinger V, Arnaud C, Cobo AM, et al. Cognitive profile in a large french cohort of adults with Prader-Willi syndrome: differences between genotypes. J Intellect Disabil Res. (2010) 54:204–15. doi: 10.1111/j.1365-2788.2010.01251.x
22. Brambilla P, Crinò A, Bedogni G, Bosio L, Cappa M, Corrias A, et al. Metabolic syndrome in children with Prader-Willi syndrome: the effect of obesity. Nutr Metab Cardiovasc Dis. (2011) 21:269–76. doi: 10.1016/j.numecd.2009.10.004
23. Crinò A, Fintini D, Bocchini S, Grugni G. Diabetes, metabolic syndrome and obesity: targets and therapy dovepress obesity management in Prader-willi syndrome: current perspectives. Diabetes Metab Syndr Obes Targets Ther. (2018) 11:579–93. doi: 10.2147/DMSO.S141352
24. Butler JV, Whittington JE, Holland AJ, Boer H, Clarke D, Webb T. Prevalence of, and risk factors for, physical ill-health in people with Prader-Willi syndrome: a population-based study. Dev Med Child Neurol. (2002) 44:248–55. doi: 10.1017/S001216220100202X
25. Whittington JE, Holland AJ, Webb T. Ageing in people with Prader-Willi syndrome: mortality in the UK population cohort and morbidity in an older sample of adults. Psychol Med. (2015) 45:615–21. doi: 10.1017/S0033291714001755
30. Mogul HR, Lee PDK, Whitman BY, Zipf WB, Frey M, Myers S, et al. Growth hormone treatment of adults with Prader-Willi syndrome and growth hormone deficiency improves lean body mass, fractional body fat, and serum triiodothyronine without glucose impairment: results from the United States multicenter trial. J Clin Endocrinol Metab. (2008) 93:1238–45. doi: 10.1210/jc.2007-2212
31. Siemensma EPC, Tummers-de Lind van Wijngaarden RFA, Festen DAM, Troeman ZCE, van Alfen-van der Velden AAEM, Otten BJ, et al. Beneficial effects of growth hormone treatment on cognition in children with Prader-Willi syndrome: a randomized controlled trial and longitudinal study. J Clin Endocrinol Metab. (2012) 97:2307–14. doi: 10.1210/jc.2012-1182
32. Berini J, Spica Russotto V, Castelnuovo P, Di Candia S, Gargantini L, Grugni G, et al. Growth hormone therapy and respiratory disorders: long-term follow-up in PWS children. J Clin Endocrinol Metab. (2013) 98:E1516–23. doi: 10.1210/jc.2013-1831
33. Deal CL, Tony M, Höybye C, Allen DB, Tauber M, Christiansen JS, et al. Growth hormone research society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. J Clin Endocrinol Metab. (2013) 98:E1072–87. doi: 10.1210/jc.2012-3888
34. Dykens EM, Roof E, Hunt-Hawkins H. Cognitive and adaptive advantages of growth hormone treatment in children with Prader-Willi syndrome. J Child Psychol Psychiatry Allied Discip. (2017) 58:64–74. doi: 10.1111/jcpp.12601
35. Crinò A, Schiaffini R, Ciampalini P, Spera S, Beccaria L, Benzi F, et al. Hypogonadism and pubertal development in Prader-Willi syndrome. Eur J Pediatr. (2003) 162:327–33. doi: 10.1007/s00431-002-1132-4
37. Muscogiuri G, Formoso G, Pugliese G, Ruggeri RM, Scarano E, Colao A. Prader- Willi syndrome: an uptodate on endocrine and metabolic complications. Rev Endocr Metab Disord. (2019) 20:239–50. doi: 10.1007/s11154-019-09502-2
38. Tauber M, Barbeau C, Jouret B, Pienkowski C, Malzac P, Moncla A, et al. Auxological and endocrine evolution of 28 children with Prader-Willi syndrome: effect of GH therapy in 14 children. Horm Res Paediatr. (2000) 53:279–87. doi: 10.1159/000053184
39. Corrias A, Grugni G, Crinò A, Di Candia S, Chiabotto P, Cogliardi A, et al. Assessment of central adrenal insufficiency in children and adolescents with Prader-Willi syndrome. Clin Endocrinol. (2012) 76:843–50. doi: 10.1111/j.1365-2265.2011.04313.x
40. Beauloye V, Dhondt K, Buysse W, Nyakasane A, Zech F, De Schepper J, et al. Evaluation of the hypothalamic-pituitary-adrenal axis and its relationship with central respiratory dysfunction in children with Prader-Willi syndrome rare endocrinological diseases. Orphanet J Rare Dis. (2015) 10:4–11. doi: 10.1186/s13023-015-0312-z
41. Grugni G, Beccaria L, Corrias A, Crinò A, Cappa M, De Medici C, et al. Central adrenal insufficiency in young adults with Prader-Willi Syndrome. Clin Endocrinol. (2013) 79:371–8. doi: 10.1111/cen.12150
45. Yazdi PG, Su H, Ghimbovschi S, Fan W, Coskun PE, Nalbandian A, et al. Differential gene expression reveals mitochondrial dysfunction in an imprinting center deletion mouse model of prader-willi syndrome. Clin Transl Sci. (2013) 6:347–55. doi: 10.1111/cts.12083
47. Butler MG, Wang K, Marshall JD, Naggert JK, Rethmeyer JA, Gunewardena SS, et al. Coding and noncoding expression patterns associated with rare obesity-related disorders: Prader-Willi and Alstrom syndromes. Adv Genomics Genet. (2015) 50:53–75. doi: 10.2147/AGG.S74598
48. Koufaris C, Alexandrou A, Papaevripidou I, Alexandrou I, Christophidou-Anastasiadou V, Sismani C. Deletion of SNURF/SNRPN U1B and U1B* upstream exons in a child with developmental delay and excessive weight. J Genet. (2016) 95:621–4. doi: 10.1007/s12041-016-0666-6
50. Christian SL, Robinson WP, Huang B, Mutirangura A, Line MR, Nakao M, et al. Molecular characterization of two proximal deletion breakpoint regions in both Prader-Willi and Angelman syndrome patients. Am J Hum Genet. (1995) 57:40–8.
51. Hartin SN, Hossain WA, Francis D, Godler DE, Barkataki S, Butler MG. Analysis of the Prader–Willi syndrome imprinting center using droplet digital PCR and next-generation whole-exome sequencing. Mol Genet Genomic Med. (2019) 7:1–10. doi: 10.1002/mgg3.575
52. Glenn CC, Driscoll DJ, Yang TP, Nicholls RD. Genomic imprinting: potential function and mechanisms revealed by the Prader-Willi and Angelman syndromes. Mol Hum Reprod. (1997) 3:321–32. doi: 10.1093/molehr/3.4.321
53. Kosaki K, McGinniss MJ, Veraksa AN, McGinnis WJ, Jones KL. Prader-Willi and Angelman syndromes: diagnosis with a bisulfite-treated methylation-specific PCR method. Am J Med Genet. (1997) 73:308–13. doi: 10.1002/(SICI)1096-8628(19971219)73:3<308::AID-AJMG15>3.0.CO;2-N
55. Bittel DC, Kibiryeva N, Butler MG. Methylation-specific multiplex ligation-dependent probe amplification analysis of subjects with chromosome 15 abnormalities. Genet Test. (2007) 11:467–76. doi: 10.1089/gte.2007.0061
56. Henkhaus RS, Kim SJ, Kimonis VE, Gold J-A, Dykens EM, Driscoll DJ, et al. Methylation-specific multiplex ligation-dependent probe amplification and identification of deletion genetic subtypes in Prader-Willi syndrome. Genet Test Mol Biomarkers. (2011) 16:178–86. doi: 10.1089/gtmb.2011.0115
57. White HE, Hall VJ, Cross NCP. Methylation-sensitive high-resolution melting-curve analysis of the SNRPN gene as a diagnostic screen for Prader-Willi and Angelman syndromes. Clin Chem. (2007) 53:1960–2. doi: 10.1373/clinchem.2007.093351
58. Ferreira IR, Darleans dos Santos Cunha W, Henrique Ferreira Gomes L, Azevedo Cintra H, Lopes Cabral Guimarães Fonseca L, Ferreira Bastos E, et al. A rapid and accurate methylation-sensitive high-resolution melting analysis assay for the diagnosis of Prader Willi and Angelman patients. Mol Genet Genomic Med. (2019) 7:1–10. doi: 10.1002/mgg3.637
60. Smith A, Lindeman R, Volpato F, Kearney A, White S, Haan E, et al. A de novo unbalanced reciprocal translocation identified as paternal in origin in the Prader-Willi syndrome. Hum Genet. (1991) 86:534–6. doi: 10.1007/BF00194651
63. Flori E, Biancalana V, Girard-Lemaire F, Favre R, Flori J, Doray B, et al. Difficulties of genetic counselling and prenatal diagnosis in a consanguineous couple segregating for the same translocation (14;15) (q11;q13) and at risk for Prader-Willi and Angelman syndromes. Eur J Hum Genet. (2004) 12:181–6. doi: 10.1038/sj.ejhg.5201134
64. Kim SJ, Miller JL, Kuipers PJ, German JR, Beaudet AL, Sahoo T, et al. Unique and atypical deletions in Prader-Willi syndrome reveal distinct phenotypes. Eur J Hum Genet. (2012) 20:283–90. doi: 10.1038/ejhg.2011.187
66. Santoro SL, Hashimoto S, McKinney A, Mihalic Mosher T, Pyatt R, Reshmi SC, et al. Assessing the clinical utility of SNP microarray for Prader-Willi syndrome due to uniparental disomy. Cytogenet Genome Res. (2017) 152:105–9. doi: 10.1159/000478921
67. Beygo J, Buiting K, Ramsden SC, Ellis R, Clayton-Smith J, Kanber D. Update of the EMQN/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes. Eur J Hum Genet. (2019) 15:1326–40. doi: 10.1038/s41431-019-0435-0
68. Torrado M, Araoz V, Baialardo E, Abraldes K, Mazza C, Krochik G, et al. Clinical-etiologic correlation in children with Prader-Willi syndrome (PWS): an interdisciplinary study. Am J Med Genet Part A. (2007) 143A:460–8. doi: 10.1002/ajmg.a.31520
69. Butler MG, Bittel DC, Bittel N, Talebizadeh KZ, Thompson T. Behavioral differences among subjects with Prader-Willi Syndrome and type I or type II deletion and maternal disomy. Pediatrics. (2004) 113:565–73. doi: 10.1542/peds.113.3.565
70. Hartley SL, MacLean WE, Butler MG, Zarcone J, Thompson T. Maladaptive behaviors and risk factors among the genetic subtypes of Prader-Willi syndrome. Am J Med Genet Part A. (2005) 136A:140–5. doi: 10.1002/ajmg.a.30771
71. Descheemaeker MJ, Govers V, Vermeulen P, Fryns JP. Pervasive developmental disorders in Prader–Willi syndrome: the Leuven experience in 59 subjects and controls. Am J Med Genet Part A. (2006) 140A:1136–42. doi: 10.1002/ajmg.a.31235
73. Whittington J, Holland A, Webb T, Butler J, Clarke D, Boer H. Cognitive abilities and genotype in a population-based sample of people with Prader-Willi syndrome. J Intellect Disabil Res. (2004) 48:172–87. doi: 10.1111/j.1365-2788.2004.00556.x
74. Yang L, Zhan G, Ding J, Wang H, Ma D, Huang G, et al. Psychiatric illness and intellectual disability in the Prader–Willi syndrome with different molecular defects - a meta analysis. PLoS ONE. (2013) 8:e72640. doi: 10.1371/journal.pone.0072640
75. Dykens EM, Roof E, Hunt-Hawkins H, Dankner N, Lee EB, Shivers CM, et al. Diagnoses and characteristics of autism spectrum disorders in children with Prader-Willi syndrome. J Neurodev Disord. (2017) 9:18. doi: 10.1186/s11689-017-9200-2
76. Jong MTC, Gray TA, Ji Y, Glenn CC, Saitoh S, Driscoll DJ, et al. A novel imprinted gene, encoding a RING Zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region. Hum Mol Genet. (1999) 8:783–93. doi: 10.1093/hmg/8.5.783
77. Valadares LP, Meireles CG, De Toledo IP, Santarem de Oliveira R, Gonçalves de Castro LC, Abreu AP, et al. MKRN3 mutations in central precocious puberty: a systematic review and meta-analysis. J Endocr Soc. (2019) 3:979–95. doi: 10.1210/js.2019-00041
79. Macedo DB, Abreu AP, Reis ACS, Montenegro LR, Dauber A, Beneduzzi D, et al. Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J Clin Endocrinol Metab. (2014) 99:E1097–103. doi: 10.1210/jc.2013-3126
81. Settas N, Dacou-Voutetakis C, Karantza M, Kanaka-Gantenbein C, Chrousos GP, Voutetakis A. Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene. J Clin Endocrinol Metab. (2014) 99:E647–51. doi: 10.1210/jc.2013-4084
82. Schaaf CP, Gonzalez-Garay ML, Xia F, Potocki L, Gripp KW, Zhang B, et al. Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism. Nat Genet. (2013) 45:1405–8. doi: 10.1038/ng.2776
84. Devos J, Weselake SV, Wevrick R. MAGEL2, a Prader-Willi syndrome candidate gene, modulates the activities of circadian rhythm proteins in cultured cells. J Circadian Rhythms. (2011) 9:12. doi: 10.1186/1740-3391-9-12
86. Myers SE, Davis A, Whitman BY, Santiago JV, Landt M. Leptin concentrations in Prader-Willi syndrome before and after growth hormone replacement. Clin Endocrinol. (2000) 52:101–5. doi: 10.1046/j.1365-2265.2000.00868.x
87. Mercer RE, Michaelson SD, Chee MJS, Atallah TA, Wevrick R, Colmers WF. MAGEL2 is required for leptin-mediated depolarization of POMC neurons in the hypothalamic arcuate nucleus in mice. PLoS Genet. (2013) 9:e1003207. doi: 10.1371/journal.pgen.1003207
93. Miller NLG, Wevrick R, Mellon PL. Necdin, a Prader-Willi syndrome candidate gene, regulates gonadotropin-releasing hormone neurons during development. Hum Mol Genet. (2008) 18:248–60. doi: 10.1093/hmg/ddn344
94. Jay P, Rougeulle C, Massacrier A, Moncla A, Mattel M, Malzac P, et al. The human necdin gene, NDN, is maternally imprinted and located in the Prader-Willi syndrome chromosomal region. Nat Genet. (1997) 17:357–61. doi: 10.1038/ng1197-357
95. Lee S, Walker CL, Karten B, Kuny SL, Tennese AA, O'Neill MA, et al. Essential role for the Prader–Willi syndrome protein necdin in axonal outgrowth. Hum Mol Genet. (2005) 14:627–37. doi: 10.1093/hmg/ddi059
96. Watrin F, Roëckel N, Lacroix L, Mignon C, Mattei MG, Disteche C, et al. The mouse Necdin gene is expressed from the paternal allele only and lies in the 7C region of the mouse chromosome 7, a region of conserved synteny to the human Prader-Willi syndrome region. Eur J Hum Genet. (1997) 5:324–32. doi: 10.1159/000484784
97. Miller J, Silverstein J, Shuster J, Driscoll DJ, Wagner M. Short-term effects of growth hormone on sleep abnormalities in Prader-Willi syndrome. J Clin Endocrinol Metab. (2006) 91:413–7. doi: 10.1210/jc.2005-1279
98. Muscatelli F. Disruption of the mouse necdin gene results in hypothalamic and behavioral alteratio ns reminiscent of the human Prader-Willi syndrome. Hum Mol Genet. (2000) 9:3101–10. doi: 10.1093/hmg/9.20.3101
99. Zanella S, Watrin F, Mebarek S, Marly F, Roussel M, Gire C, et al. Necdin plays a role in the serotonergic modulation of the mouse respiratory network: implication for Prader-Willi syndrome. J Neurosci. (2008) 28:1745–55. doi: 10.1523/JNEUROSCI.4334-07.2008
100. Kanber D, Giltay J, Wieczorek D, Zogel C, Hochstenbach R, Caliebe A, et al. A paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader-Willi syndrome. Eur J Hum Genet. (2009) 17:582–90. doi: 10.1038/ejhg.2008.232
102. Pagliardini S, Ren J, Wevrick R, Greer JJ. Developmental abnormalities of neuronal structure and function in prenatal mice lacking the Prader-Willi syndrome gene necdin. Am J Pathol. (2005) 167:175–91. doi: 10.1016/S0002-9440(10)62964-1
103. Dhanoa JK, Sethi RS, Verma R, Arora JS, Mukhopadhyay CS. Long non-coding RNA: its evolutionary relics and biological implications in mammals: a review. J Anim Sci Technol. (2018) 60:25. doi: 10.1186/s40781-018-0183-7
106. Buiting K, Nazlican H, Galetzka D, Wawrzik M, Groβ S, Horsthemke B. C15orf2 and a novel noncoding transcript from the Prader–Willi/Angelman syndrome region show monoallelic expression in fetal brain. Genomics. (2007) 89:588–95. doi: 10.1016/j.ygeno.2006.12.008
107. Wawrzik M, Spiess A-N, Herrmann R, Buiting K, Horsthemke B. Expression of SNURF–SNRPN upstream transcripts and epigenetic regulatory genes during human spermatogenesis. Eur J Hum Genet. (2009) 17:1463–70. doi: 10.1038/ejhg.2009.83
108. Chen Z, Ju H, Yu S, Zhao T, Jing X, Li P, et al. Prader–Willi region non-protein coding RNA 1 suppressed gastric cancer growth as a competing endogenous RNA of MiR-425-5p. Clin Sci. (2018) 132:1003–19. doi: 10.1042/CS20171588
110. Lee S, Wevrick R. Identification of novel imprinted transcripts in the Prader-Willi syndrome and angelman syndrome deletion region: further evidence for regional imprinting control. Am J Hum Genet. (2000) 66:848–58. doi: 10.1086/302817
111. Färber C, Groß S, Neesen J, Buiting K, Horsthemke B. Identification of a testis-specific gene (C15orf2) in the Prader–Willi syndrome region on chromosome 15. Genomics. (2000) 65:174–83. doi: 10.1006/geno.2000.6158
112. Neumann LC, Markaki Y, Mladenov E, Hoffmann D, Buiting K, Horsthemke B. The imprinted NPAP1/C15orf2 gene in the Prader–Willi syndrome region encodes a nuclear pore complex associated protein. Hum Mol Genet. (2012) 21:4038–48. doi: 10.1093/hmg/dds228
114. Özçelik T, Leff S, Robinson W, Donlon T, Lalande M, Sanjines E, et al. Small nuclear ribonucleoprotein polypeptide N (SNRPN), an expressed gene in the Prader–Willi syndrome critical region. Nat Genet. (1992) 2:265–9. doi: 10.1038/ng1292-265
115. Rodriguez-Jato S, Nicholls RD, Driscoll DJ, Yang TP. Characterization of cis- and trans-acting elements in the imprinted human SNURF-SNRPN locus. Nucleic Acids Res. (2005) 33:4740–53. doi: 10.1093/nar/gki786
116. Cao Y, AlHumaidi SS, Faqeih EA, Pitel BA, Lundquist P, Aypar U. A novel deletion of SNURF/SNRPN Exon 1 in a patient with Prader-Willi-like phenotype. Eur J Med Genet. (2017) 60:416–20. doi: 10.1016/j.ejmg.2017.05.003
118. Cavaillé J, Buiting K, Kiefmann M, Lalande M, Brannan CI, Horsthemke B, et al. Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization. Proc Natl Acad Sci USA. (2000) 97:14311–6. doi: 10.1073/pnas.250426397
119. Castle JC, Armour CD, Löwer M, Haynor D, Biery M, Bouzek H, et al. Digital genome-wide NcRNA expression, including SnoRNAs, across 11 human tissues using polyA-neutral amplification. PLoS ONE. (2010) 5:e11779. doi: 10.1371/journal.pone.0011779
120. Chamberlain SJ, Chen PF, Ng KY, Bourgois-Rocha F, Lemtiri-Chlieh F, Levine ES, et al. Induced pluripotent stem cell models of the genomic imprinting disorders angelman and Prader-Willi Syndromes. Proc Natl Acad Sci USA. (2010) 107:17668–73. doi: 10.1073/pnas.1004487107
121. Martins-Taylor K, Hsiao JS, Chen P-F, Glatt-Deeley H, De Smith AJ, Blakemore AIF, et al. Imprinted expression of UBE3A in non-neuronal cells from a Prader–Willi syndrome patient with an atypical deletion. Hum Mol Genet. (2014) 23:2364–73. doi: 10.1093/hmg/ddt628
122. Vitali P, Royo H, Marty V, Bortolin-Cavaille M-L, Cavaille J. Long nuclear-retained non-coding RNAs and allele-specific higher-order chromatin organization at imprinted snoRNA gene arrays. J Cell Sci. (2010) 123:70–83. doi: 10.1242/jcs.054957
123. Cavaillé J. Box C/D small nucleolar RNA genes and the Prader-Willi syndrome: a complex interplay: box C/D SnoRNA genes and the Prader-Willi syndrome. Wiley Interdiscipl. Rev. RNA. (2017) 8:e1417. doi: 10.1002/wrna.1417
124. Zhang YJ, Yang JH, Shi QS, Zheng LL, Liu J, Zhou H, et al. Rapid birth-and-death evolution of imprinted snoRNAs in the Prader-Willi syndrome locus: implications for neural development in Euarchontoglires. PLoS ONE. (2014) 9:e100329. doi: 10.1371/journal.pone.0100329
125. Bieth E, Eddiry E, Gaston V, Lorenzini F, Buffet A, Conte AF, et al. Highly restricted deletion of the SNORD116 region is implicated in Prader–Willi syndrome. Eur J Hum Genet. (2015) 23:252–5. doi: 10.1038/ejhg.2014.103
126. Duker AL, Ballif BC, Bawle EV, Person RE, Mahadevan S, Alliman S, et al. Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box SnoRNA cluster in Prader–Willi syndrome. Eur J Hum Genet. (2010) 18:1196–201. doi: 10.1038/ejhg.2010.102
127. Sahoo T, del Gaudio D, German JR, Shinawi M, Peters SU, Person RE, et al. Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat Genet. (2008) 40:719–21. doi: 10.1038/ng.158
128. de Smith AJ, Purmann C, Walters RG, Ellis RJ, Holder SE, Van Haelst MM, et al. A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism. Hum Mol Genet. (2009) 18:3257–65. doi: 10.1093/hmg/ddp263
129. Ding F, Li HH, Zhang S, Solomon NM, Camper SA, Cohen P, et al. SnoRNA SNORD116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice. PLoS ONE. (2008) 3:e1709. doi: 10.1371/journal.pone.0001709
131. Rozhdestvensky TS, Robeck T, Galiveti CR, Raabe CA, Seeger B, Wolters A, et al. Maternal transcription of non-protein coding RNAs from the PWS-critical region rescues growth retardation in mice. Sci Rep. (2016) 6:20398. doi: 10.1038/srep20398
132. Skryabin BV, Gubar LV, Seeger B, Pfeiffer J, Handel S, Robeck T, et al. Deletion of the MBII-85 snoRNA gene cluster in mice results in postnatal growth retardation. PLoS Genet. (2007) 3:e235. doi: 10.1371/journal.pgen.0030235
133. Burnett LC, LeDuc CA, Sulsona CR, Paull D, Rausch R, Eddiry S, et al. Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome. J Clin Invest. (2017) 127:293–305. doi: 10.1172/JCI88648
134. Coulson RL, Yasui DH, Dunaway KW, Laufer BI, Vogel Ciernia A, Zhu Y, et al. Snord116-dependent diurnal rhythm of DNA methylation in mouse cortex. Nat Commun. (2018) 9:1616. doi: 10.1038/s41467-018-03676-0
135. Bürger J, Horn D, Tönnies H, Neitzel H, Reis A. Familial interstitial 570 Kbp deletion of the UBE3A gene region causing angelman syndrome but not Prader-Willi syndrome: familial UBE3A gene deletion. Am J Med Genet. (2002) 111:233–7. doi: 10.1002/ajmg.10498
136. Runte M, Varon R, Horn D, Horsthemke B, Buiting K. Exclusion of the C/D box snoRNA gene cluster HBII-52 from a major role in Prader? Willi syndrome. Hum Genet. (2005) 116:228–30. doi: 10.1007/s00439-004-1219-2
137. Stelzer Y, Sagi I, Yanuka O, Eiges R, Benvenisty N. The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome. Nat Genet. (2014) 46:551–7. doi: 10.1038/ng.2968
139. Ding F, Prints Y, Dhar MS, Johnson DK, Montero CC, Nicholls RD, et al. Lack of Pwcr1/MBII-85 SnoRNA is critical for neonatal lethality in Prader–Willi syndrome mouse models. Mammalian Genome. (2005) 16:424–31. doi: 10.1007/s00335-005-2460-2
140. Falk MJ, Curtis C, Bass NE, Zinn AB, Schwartz S. Maternal uniparental disomy chromosome 14: case report and literature review. Pediatric Neurol. (2005) 32:116–20. doi: 10.1016/j.pediatrneurol.2004.07.007
141. Hordijk R, Wierenga H, Scheffer H, Leegte B, Hofstra R, Stolte-Dijkstra I. Maternal uniparental disomy for chromosome 14 in a boy with a normal karyotype. J Med Genet. (1999) 36:782–5. doi: 10.1136/jmg.36.10.782
142. Hosoki K, Kagami M, Tanaka T, Kubota M, Kurosawa K, Kato M, et al. Maternal Uniparental Disomy 14 Syndrome Demonstrates Prader-Willi Syndrome-Like Phenotype. J Pediatr. (2009) 155:900–03.e1. doi: 10.1016/j.jpeds.2009.06.045
144. Patten MM, Cowley M, Oakey RJ, Feil R. Regulatory links between imprinted genes: evolutionary predictions and consequences. Proc R Soc B Biol Sci. (2016) 283:20152760. doi: 10.1098/rspb.2015.2760
145. Wold EA, Wild CT, Cunningham KA, Zhou J. Targeting the 5-HT2C receptor in biological context and the current state of 5-HT2C receptor ligand development. Curr Top Med Chem. (2019) 19:1381–98. doi: 10.2174/1568026619666190709101449
146. Nonogaki K, Strack AM, Dallman MF, Tecott LH. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med. (1998) 4:1152–6. doi: 10.1038/2647
151. Kim Y, Lee H-M, Xiong Y, Sciaky N, Hulbert SW, Cao X, et al. Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome. Nat Med. (2017) 23:213–22. doi: 10.1038/nm.4257
Keywords: Prader-Willi syndrome, genotype, phenotype, endocrine, imprinting, SNORDs
Citation: Costa RA, Ferreira IR, Cintra HA, Gomes LHF and Guida LdC (2019) Genotype-Phenotype Relationships and Endocrine Findings in Prader-Willi Syndrome. Front. Endocrinol. 10:864. doi: 10.3389/fendo.2019.00864
Received: 30 September 2019; Accepted: 26 November 2019;
Published: 13 December 2019.
Edited by:Ana Rosa Pérez, National Council for Scientific and Technical Research, Argentina
Reviewed by:Christian P. Schaaf, Heidelberg University, Germany
Dag H. Yasui, University of California, Davis, United States
Copyright © 2019 Costa, Ferreira, Cintra, Gomes and Guida. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Letícia da Cunha Guida, firstname.lastname@example.org
†These authors have contributed equally to this work