Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development

Abstract

The RNA helicase DHX37 gene is involved in ribosomal biological processes, and linked to human genetic diseases associated with 46,XY disorders of sex development (46,XY DSD) or neurodevelopment. Recently, relevant reports have primarily focused on 46,XY DSD. However, there is still a lack of overall understanding of the genetic characteristics, phenotype, etc. of the DHX37 gene in human genetic diseases, and its molecular mechanism is not fully understood. We searched literature databases and summarized and analyzed all the literature related to DHX37 to date, including case reports, cohort studies, and molecular mechanism studies, to comprehensively demonstrate the role of DHX37 in human genetic diseases. Sixty patients were reported to have DHX37-related 46,XY DSD, with p.R308Q, p.R674W variants being the two most common mutation hotspots, accounting for 36.67% and 11.67% of cases respectively. In DSD cohorts, DHX37 gene mutations have different detection frequencies (0.77%–45.45%), whereas in testicular regression syndrome and 46,XY gonadal dysgenesis cohorts, they have a high detection rate. The gonadal development and fertility of female (46,XX) carriers with DHX37 gene mutations are not affected; however, incomplete penetrance may be observed in males (46,XY). The treatments are primarily surgical intervention and hormone replacement therapy administered at appropriate times; however, the long-term prognosis remains unknown. Although the molecular mechanism of DHX37 mutation related 46,XY DSD is unclear, ribosome synthesis, cell cycle regulation, and the NF-κB and Wnt pathways may be affected. This review summarizes the profile of DHX37 defects in human genetic diseases.

1 Overview of DHX37 gene mutations in genetic diseases

DHX37 (NM_032656.4) belongs to the DexD/H-box RNA helicase family, a conserved protein group with an Asp-Glu-Ala-Asp motif (DEAD) (1). DHX37 is associated with 46,XY disorders of sex development (46,XY DSD; 46,XY sex reversal 11 in OMIM #273250) as autosomal dominant inheritance, and developmental delay (“neurodevelopmental disorder with brain anomalies, with or without vertebral or cardiac anomalies” in OMIM #618731) as autosomal recessive inheritance (2, 3). We searched PubMed, Embase, and other literature databases and referred to the ClinVar gene variation database to summarize and display the DHX37 gene variations and related clinical phenotype diagrams in Figure 1. There were 11 cohort studies and 6 case reports on DHX37-related 46,XY DSD, along with a little articles on neurodevelopmental disorders. We observed that the reported pathogenic or likely pathogenic mutations were mainly missense mutations, with only one frameshift mutation mentioned (Figure 1A). This characteristic is consistent across the phenotypes of 46,XY DSD or neurological system related phenotypes. Furthermore, another substantial feature of these variants is that mutations associated with both 46,XY DSD and the neurological system are highly concentrated in the two primary functional domains of DHX37, RecA1 (262-429 amino acid) and RecA2 (459-716 amino acid. The data is sourced from the InterPro and UniProt databases, website: https://www.ebi.ac.uk/interpro/protein/UniProt/Q8IY37/ and https://www.uniprot.org/uniprotkb/Q8IY37/entry). Although a greater number of variants have been reported to be associated with 46, XY DSD, there is no significant difference in the distribution of variants related to neurodevelopmental disorder in the domain structure.

Figure 1

This study mainly focuses on the situation of DHX37 in 46,XY DSD related fields. Of the 25 mutation sites associated with 46,XY DSD, 16 were located within these two domains. The RecA2 region has a higher frequency of mutations. Regarding the DHX37-related 46,XY DSD external genital phenotypes, micropenis was present in the majority of variant phenotypes, commonly accompanied by cryptorchidism. Both symptoms are widely present in mutations located within the RecA1 and RecA2 regions. Mutations in the RecA1 region display a broader range of external genitalia phenotypes, including clitoromegaly, absent vaginal opening, and hypospadias, which encompass more “female” phenotypes. Mutations in RecA2 predominantly manifest as micropenis and cryptorchidism. This characteristic combination is commonly observed in mutations affecting both the RecA1 and RecA2 regions of the DHX37 gene. The co-occurrence of these two phenotypic features suggests a possible shared underlying mechanism in the developmental pathways influenced by mutations in these regions, potentially affecting penile growth and testicular descent. Regarding the internal genitalia, most mutations clustered in these two regions showed the absence of Müllerian structures, whereas Wolffian structures were present in some cases.

Sixty patients were reported to carry DHX37 variants related to 46,XY DSD, with a total of 25 variant sites. Among them, the p.R308Q variant had the highest frequency, accounting for 36.67% (22/60); the p.R674W variant accounted for 11.67% (7/60); p.T304W variant;accounted for 5% (3/60); p.R334W, p.S408L, p.T477M, p.S595F, p.R674Q and p.V999M variants accounted for 3.33% (2/60) each; and the other 16 mutations, p.I254V, p.R334L, p.G386S, p.R390H, p.L467V, p.G478R, p.R487H, p.A492P, p.D506N, p.S626L, p.L627F, p.T727fs, p.A737T, p.N900D, p.Q921R and p.G1030E, accounted for 1.67% (1/60) each (Figure 1B). The two most common variants, p.R308Q and p.R674W, classified by the American College of Medical Genetics and Genomics classification as pathogenic (P) or likely pathogenic (LP), were located in the RecA1 and RecA2 regions, respectively. This aligns with our previous assertion that mutations within the RecA1 region tend to manifest more severe and diverse phenotypes. This distribution pattern highlights the potential functional importance of these specific amino acid positions within the DHX37 protein and their impact on sexual development. The clinical manifestations of the p.R308Q mutation locus include micropenis, cryptorchidism, hypoplasia of testicular tissue, testicular fibrosis, blurring of genitalia, and other clinical manifestations, such as clitoral hypertrophy and labial fusion in female patients without other systemic changes.

2 Variations of DHX37 gene in 46,XY DSD cohorts

The first confirmation of an association between DHX37 gene defect and 46,XY DSD was found via genetic screening of cohorts in 2019. In the cohort of 87 patients diagnosed with 46,XY DSD, including 55 patients with 46,XY GD and 32 patients with 46,XY DSD, after ruling out LHCGR, AR, CYP17A1, HSD17B3, HSD3B2, and SRD5A2 gene defects, there were 17 patients with the “P” or “LP” mutation of DHX37 gene, with a mutation frequency of 19.54% (17/87). Among the 14 patients with embryonic regression testicular syndrome (ETRS) in this cohort, seven had DHX37 mutations, suggesting that DHX37 may be the main molecular cause of ETRS (50%, 7/14) (2). In another 46,XY DSD cohort of 145 patients, 13 (13/145, 8.97%) had a DHX37 mutation. Of the 81 patients with 46,XY GD, nine carried a DHX37 mutation (9/81, 11%), whereas in 16 patients with 46,XY testicular regression syndrome (TRS), four carried a DHX37 mutation (4/16, 25%) (4). The above two cohort studies established that DHX37 mutation is one reason of 46,XY DSD, and is more common in TRS. In a small cohort of patients with TRS and partial gonadal dysplasia (PGD) in Japan (n=11), five patients (5/11, 45.45%) had DHX37 mutations based on NGS-panel detection (5). In five ETRS patients from China, two of them (40%, 2/5) were detected p.R308Q of DHX37 at two months old and one year and 5 months old (6). In a 46,XY PGD cohort (n=25) from the United Kingdom and Chile, the DHX37 mutation accounted for 16% (4/25), ranking second only to NR5A1 gene mutation frequency (20%) (7). Using whole-exome sequencing (WES) in 140 patients with 46,XY DSD, DHX37 mutations were detected in seven (7/140, 5%), with clinical phenotypes involving TRS (five patients), complete gonadal dysplasia (CGD) (one patient), and 46,XY DSD (one patient) (8). This study expanded the phenotype of 46,XY DSD caused by DHX37 gene mutation by adding CGD. In a subsequent cohort of 46,XY CGD, a 31-year-old “female” with primary amenorrhea from the 46,XY “female” cohort (n=25) presented with ambiguous genitalia, Tanner stage as B1P3A2, Müllerian absence, ovaries absence, and a follicle stimulating hormone (FSH) level of 86.56 mIU/mL (normal range 2.5–10 mIU/mL). This patient had a 46,XY chromosome karyotype and DHX37 c.1877C>T, p.S626L mutation (9). In a Brazilian cohort of 209 cases of 46,XY DSD, four patients carried DHX37 “P” or “LP” mutations, with a frequency of 1.91% (4/209), identified using Sanger sequencing or massively parallel sequencing. Three additional patients were found to carry VUSs in DHX37, including two with mutations in other genes, which cannot be confirmed as a monogenic genetic cause. The detection frequency of DHX37 mutation ranked sixth in this cohort (10). In a study of 54 Chinese 46,XY DSD cohorts, four patients carried the DHX37 pathogenic variants detected using WES, with the fourth highest detection frequency of 7.41% (4/54). The top three detected genes were AR, SRD5A2, and NR5A1 (11). There have also been reports of DHX37 mutations in a posterior hypospadias cohort (2.38%, 1/42) (12). In a DSD cohort from Ukraine, WES was performed on 79 cases of 46,XY DSD, and the DHX37 p.R674Q variant was detected in a three-year-old female patient (1/79, 1.27%) with an inguinal hernia and bilateral vesicoureteral reflux (13). In some patients, excised gonadal tissues were not pathologically examined before molecular diagnostic confirmation, and the extent of gonadal tissue differentiation and development is unknown. Notably, patients with the p.R308Q variant in some cohorts are almost exclusively females, who often present with primary amenorrhea, no uterine or ovarian tissue, enlarged clitoris, underdeveloped labia, and, in some cases, a vagina. These cohorts included female patients with 46,XY DSD of unknown etiology (4) and excluded patients with 17ß-hydroxysteroid dehydrogenase 3 deficiency, 5α-reductase type 2 deficiency, androgen insensitivity syndrome (7). In a cohort with 521 primary spermatogenic failure (SPGF) patient, 64 (12.28%, 64/521) men were molecular diagnosed finding in 39 genes, using clinical exomes sequencing. There were 4 patients carried DHX37 mutations as p.G386S, p.T727Dfs*60, p.N900D, p.Q921R (14). Overall, 12 studies of the 46,XY DSD cohort that mentioned different DHX37 variations are shown in Table 1. The overall detection rate of 46,XY DSD was 12.280%–81.82%, whereas the detection rate of DHX37 mutations was 0.77–45.45% in the differential cohort, which had various inclusion and exclusion criteria and patient numbers. Patients whose testes were not present in the scrotum or inguinal region on imaging or laparoscopic exploration, whose abdominal exploration showed testicular atrophy or gonadal dysgenesis, and whose anti-Müllerian hormone levels were below normal were included. This suggests that, in the presence of the above conditions, along with laboratory and imaging tests, genetic testing is necessary to determine whether a patient has gonadal dysgenesis. Variants in the DHX37 gene were found in TRS and 46,XY GD cohorts, with a high rate of detection. For 46,XY GD, various studies have confirmed that variants in NR5A1, SRY, and MAP3K1 are the most common causes of non-syndromic GD, with DHX37 mutations also showing a relatively high detection frequency. For TRS or ETRS, DHX37 mutation is the main genetic molecular etiology, accounting for 25%–50%; however, the sample sizes of the relevant TRS/ETRS cohorts were relatively small, necessitating large-scale screening.

3 Non-impact of DHX37 on 46,XX females

Table 2 summarizes the profiles of female carriers. None had any clinical manifestations of DSD, and they were capable of normal reproduction. Thirteen families had 15 female individuals carrying the “P” or “LP” variant of the DHX37 gene who were not affected and could have a normal pregnancy. However, male offspring who inherited the DHX37 gene variant exhibited the DSD phenotype, And the mutation sites include p.R308Q, p.L467V, p.R674W, p.R671T, p.G478R, p.R627F, and p.S595F (2, 8, 15–18). This suggests that the DHX37 mutation does not affect gonadal development in females with 46,XX. Therefore, this gene mutation should be mentioned during genetic counseling to avoid passing the mutation to offspring, which will lead to gonadal dysgenesis, burdening the family and child.

There was no significant difference in the expression of DHX37 between XX and XY individuals in the sex-determining embryonic gonads of mice (4). In human fetal testicular tissue, DHX37 is detected in Sertoli cells and some spermatogonia, but not in germ cells (2). The DHX37 gene may only function after sex differentiation, following the SRY gene, and simultaneously with SOX8 or SOX9 (19), which may be the main reason why it only affects gonadal development in 46,XY individuals but exerts no effect on 46,XX individuals.

4 Incomplete penetrance in 46,XY males

Several cases of male carriers (the father of the proband) with no evident phenotype or with normal fertility have been reported. In a Brazilian family, there were two male siblings with 46,XY DSD (ETRS, micropenis, and non-palpable) caused by the p.R308Q mutation in DHX37. Their father also carried the p.R308Q mutation but exhibited no related phenotype and had three healthy children (2). A French patient with 46,XY DSD (TRS) had a p.T477M homozygous mutation in DHX37, inherited from both parents, the fertile father of this patient was noted to have unilateral testicular agenesis (8). In an Algerian patient with 46,XY DSD, the main clinical manifestations were micropenis, bilateral cryptorchidism, non-palpable gonads, and poorly developed, fused labia caused by the p.R487H mutation in DHX37, inherited from a phenotypically an asymptomatic father (8). DHX37 mutations may also result in incomplete penetrance in males with 46,XY.

5 Molecular mechanism of DHX37 gene mutation causing disease

The majority of members of the RNA helicase family have been reported to be associated with neurological diseases (20, 21), and DHX37 is currently the only helicase gene that is associated with both neurological disorders and DSD (2, 22), its molecular mechanisms have been reported very little. In pseudomales (female-to-male sex reversals) of the Chinese tongue sole (Cynoglossus semilaevis), the expression of DHX37 and other Z chromosome-specific genes, which are important for spermatogenesis maintenance, is lower than that in normal males (23). In zebrafish, DHX37 can interact with GlyR1,3,4a transcripts, and DHX37 gene defects (dhx37^nig1 mutation) can cause splicing defects in the transcription process of GlyR1,3,4a subunits. The defects can also reduce mRNA levels and regulate glycinergic synaptic transmission, leading to an abnormal motor response (24). UTP14A activates the ATPase activity of DHX37 by binding to its carboxyl-terminal domain via conserved regions, thereby enhancing the binding of DHX37 to RNA and promoting ribosome synthesis (25). Activated DHX37 can displace box C/D snoRNA U3 from pre-ribosomal particles to ensure correct and orderly folding of ribosomal subunits (26, 27). In hepatocellular carcinoma cells, DHX37 is highly expressed and promotes proliferation and cancer progression by interacting with PLRG1 and activating the expression of CCND1 (28). In human CD8 T cells, DHX37 could be a regulator affecting NF-κB signaling, T cell activation, and cytotoxicity (29). Nuclear stress, transient activation of the Wnt pathway, and elevated P53 have also been reported in individuals with DHX37 defects (30). Overall, the pathogenic molecular mechanisms of DHX37 and 46,XY DSD are not fully understood. These mechanisms may be involved in ribosome synthesis, cell cycle regulation, and the NF-κB and Wnt pathways. It is currently unclear how this gene is integrated into the genetic network of differences in sexual development; therefore, further validation experiments are required.

6 Treatment of patients with 46,XY DSD associated with DHX37 mutation

The treatment of 46,XY DSD related to DHX37 deficiency is very difficult; there are currently no specific treatment methods available, with very limited reference cases (5, 31). We reviewed all current publications and only six cases with specific treatments have been reported, as summarized in Table 3. Surgical procedures, such as testicular fixation or orchidectomy, are one of the main coping strategies to avoid malignant changes in gonadal tissue; however, there has been no significant improvement in testicular function after surgery. Androgen therapy is also necessary and can help increase the penis size of patients to some extent, maintain normal adrenal function, and support pubertal development; however, it cannot improve fertility. Patients who present as female usually need to undergo external genital plastic surgery. Detailed prognostic and follow-up information is lacking, possibly because DHX37 has only been associated with 46,XY DSD in the last few years, and documenting the dynamic development of infants, children, and adolescents is time-consuming and labor-intensive. Molecular mutations can lead to diseases, and only treatment at the genetic level can truly solve this problem. With advancements in science and technology, and the deepening of knowledge on genetic diseases, we look forward to a cure for genetic diseases in the future.

7 Conclusion

In summary, sixty patients had DHX37-related 46,XY DSD, with a total of 25 variant sites. The p.R308Q and p.R674W variants were the two most common mutation hotspots, accounting for 36.67% and 11.67% of cases, respectively. The gonadal development and fertility of female (46,XX) carriers of DHX37 mutations are not affected; however, incomplete penetrance may be observed in males (46,XY). In DSD cohorts, DHX37 gene mutations have different detection frequencies (0.77%–45.45%), whereas in TRS and 46,XY GD cohorts, they have a high rate of detection. The molecular mechanism of DHX37 pathogenesis, the specific pathways of action, and target molecules remain uncertain; however, ribosome synthesis, cell cycle regulation, and the NF-κB and Wnt pathways are suspected to be involved. Surgical intervention and appropriate timing of hormone replacement therapy are commonly used for DHX37-related 46,XY DSDs, although there are limited reported cases. The maintenance of male function and fertility after treatment remains unknown. Gene therapy for genetic diseases may provide new opportunities for the treatment of these diseases in the future.

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