Congenital cataracts, an ophthalmic disease presented at birth or developing in infancy, can lead to a clouding in the lens of the eye that can cause blurry vision or blindness (1–3). As the predominant cause of visual impairment and blindness among children, congenital cataracts affect approximately 200,000 children worldwide, with an estimated prevalence ranging from three to six per 10,000 live births (4, 5). The current studies believe that multiple factors including genetics, infections, radiation exposure, toxic agents, and metabolic disturbance underlie the occurrence of congenital cataracts (3). To date, over 40 genes responsible for the molecular etiology of isolated or syndromic congenital cataracts, featuring autosomal dominant or autosomal recessive inheritance patterns, have been identified (1, 6).

The V-MAF avian musculoaponeurotic-fibrosarcoma oncogene homolog (MAF) gene, also known as MAF bZIP transcription factor (OMIM#177075), is situated on chromosome 16q23.2, spanning approximately 6.9 kilobases (7). As a DNA-binding transcription factor with a leucine zipper motif that can control the activity of target genes, MAF can serve as a transcriptional activator or repressor, regulating diverse cellular processes, including embryonic lens fiber cell development, heightened T-cell susceptibility to apoptosis, and chondrocyte terminal differentiation (8–10). In 2002, Jamieson et al. (11) initially reported the association of MAF with cataracts, ocular anterior segment dysgenesis, and coloboma. Subsequently, approximately 30 MAF mutations have been detected in patients with Ayme-Gripp syndrome and isolated cataracts (7).

Here, we recruited a Chinese family affected by isolated congenital cataracts. Utilizing whole exome sequencing and Sanger sequencing, we sought to uncover the genetic abnormalities in the affected individuals.

Here, we enrolled the family from Hebei province, China (Figure 1A). The affected proband, a four-year-old boy was admitted to Hebei General Hospital and diagnosed as a total congenital cataract of the right eye (Figure 1B). A medical history survey suggested that the patient suffered from poor vision in dim light at approximately 3 years old but did not arouse parents’ attention, and the symptoms of the child developed to lens complete opacification from pupil gray appearance quickly during this year. Finally, the patient agreed to undergo surgery for cataract extraction and implantation for the posterior chamber intraocular lens, and the eye vision is gradually recovering. A study of the family history indicated that his father also suffered from cataracts and underwent cataract extraction in infancy. The proband’s grandmother was blind and died several years ago.

Congenital cataracts represent a highly diverse ocular disorder both clinically and genetically (3). Mutations in MAF have been linked to various types and severities of human congenital cataracts (Table 2) (32). MAF proteins play a pivotal role in eyes and lens development, regulating the expression of crystallin genes, MIP (major intrinsic protein of the ocular lens fiber membrane), and other genes expressed in lens fiber cells from the formation of the lens pre-placode to the development of lens fiber cells and lens epithelium (8–10). In C57BL/6J mice, homozygous deletion of MAF results in embryonic lethality, but the lens fiber cell MAF condition knockout mice (MAF^ΔTAM) develops abnormal lens structure, and the expression of crystallin genes in MAF^ΔTAM mice eyes are reduced compared to WT mice (33). The mice data were consistent with human genetic studies, highlighting the essential role of MAF in the differentiation and cell cycle arrest of lens fiber cells. Although the first mutation of MAF was reported in 2002 (11), the MAF novel mutation was rarely reported in recent years. Here, we identified a new variant (NM_005360, c.901T>C/p.Y301H) of MAF in a Chinese family with congenital cataracts via whole exome sequencing and Sanger sequencing. Our study expanded the mutation spectrum of MAF and further proved that mutations in MAF may lead to congenital cataracts.

The MAF protein consists of an N-terminal transactivation domain with a regulatory function and a C-terminal DNA binding domain (18). The C-terminal domain is further divided into three conserved regions (Figure 2A): extended homology region, basic region motif, and leucine zipper motif (15, 34). Earlier studies have indicated that the N-terminal variants may result in Ayme-Gripp syndrome which presents with cataracts, hearing loss, epilepsy, intellectual disability, etc., while most of the C-terminal mutation carriers only showed ocular diseases such as cataracts (Table 2) (7). Here, the mutation (p.Y301H) is also situated in the C-terminal of MAF, which provides more evidence that C-terminal mutations are responsible for isolated cataracts.

Furthermore, the p.Y301H mutation is in the BR motif of the C-terminal, which is the mutational hot spot region of MAF (7). Previous studies have suggested that the BR motif is responsible for binding the specific target promoters of crystallin genes including CRYGA, CRYAA, CRYBA1, and CRYBA4, which are associated with inherited cataracts (32, 35). Additionally, ChIP-seq studies have identified several non-crystallin genes crucial for maintaining lens transparency as direct targets of MAF (36, 37). Hence, the p.Y301H mutation may disrupt the bindings between MAF and the target genes such as crystallin genes, and finally disrupt the expression of promoters of crystallin genes, leading to congenital cataracts. Following the ACMG guideline (38), the p.Y301H mutation is likely pathogenic (PM1 + PM2 + PP1 + PP2 + PP3).

Congenital cataracts persist as a leading cause of global blindness, and early surgical intervention, prolonged postoperative amblyopia training, and visual reconstruction constitute the primary therapeutic approaches for the disease (39, 40). Early diagnosis is paramount, particularly in the era of precision medicine, where technologies such as PCR, Sanger sequencing, high-throughput sequencing, and gene editing have facilitated the discovery of numerous pathogenic genes linked to congenital cataract development. This advancement enhances our understanding of the disease’s pathogenesis and lays the groundwork for genetics-based treatments (6, 28). In the future, we can develop a genetic detection panel that contains all the reported mutations of MAF including the p.Y301H, and the panel may contribute to the genetic counseling and early diagnosis of congenital cataract patients.

Hence, we detected a new mutation (NM_005360, c.901T>C/p.Y301H) of MAF in a Chinese family with congenital cataracts by employing whole exome sequencing and Sanger sequencing. Our study not only explores the genetic lesion of the family and broadens the spectrum of MAF mutations but also confirms that the MAF mutation was linked to non-syndromic total congenital cataracts and facilitates genetic counseling and early diagnosis for congenital cataract patients. Certainly, there were still some limitations in this study, for example, the sample size was small and population specificity was not excluded.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving humans were approved by the Ethics Committee of Hebei General Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.

Z-JL: Data curation, Formal analysis, Writing – original draft. J-YL: Formal analysis, Writing – review & editing. JL: Resources, Writing – review & editing. F-NW: Resources, Writing – review & editing. WC: Resources, Writing – review & editing. LZ: Formal analysis, Funding acquisition, Writing – original draft. Y-LL: Funding acquisition, Resources, Writing – original draft. L-LF: Funding acquisition, Supervision, Writing – original draft, Writing – review & editing.