PAX6 Mutations Research Articles

Pax protein depletion in proximal tubules triggers conserved mechanisms of resistance to acute ischemic kidney injury preventing transition to chronic kidney disease

Acute kidney injury (AKI) is a common condition that lacks effective treatments. In part, this shortcoming is due to an incomplete understanding of the genetic mechanisms that control pathogenesis and recovery. Identifying the molecular and genetic regulators unique to nephron segments that dictate vulnerability to injury and regenerative potential could lead to new therapeutic targets to treat ischemic kidney injury. Pax2 and Pax8 are homologous transcription factors with overlapping functions that are critical for kidney development and are re-activated in AKI. Here, we examined the role of Pax2 and Pax8 in recovery from ischemic AKI and found them upregulated after severe AKI and correlated with chronic injury. Surprisingly, proximal-tubule-selective deletion of Pax2 and Pax8 resulted in a less severe chronic injury phenotype. This effect was mediated by protection against the acute insult, similar to pre-conditioning. Prior to injury, Pax2 and Pax8 mutant mice develop a unique subpopulation of proximal tubule cells in the S3 segment that displayed features usually seen only in acute or chronic injury. The expression signature of these cells was strongly enriched with genes associated with other mechanisms of protection against ischemic AKI including caloric restriction, hypoxic pre-conditioning, and female sex. Thus, our results identified a novel role for Pax2 and Pax8 in mature proximal tubules that regulates critical genes and pathways involved in both the injury response and protection from ischemic AKI.

Characterization of neural damage and neuroinflammation in Pax6 small-eye mice

Aniridia is a panocular condition characterized by a partial or complete loss of the iris. It manifests various developmental deficits in both the anterior and posterior segments of the eye, leading to a progressive vision loss. The homeobox gene PAX6 plays an important role in ocular development and mutations of PAX6 have been the main causative factors for aniridia. In this study, we assessed how Pax6-haploinsufficiency affects retinal morphology and vision of Pax6Sey mice using in vivo and ex vivo metrics. We used mice of C57BL/6 and 129S1/Svlmj genetic backgrounds to examine the variable severity of symptoms as reflected in human aniridia patients. Elevated intraocular pressure (IOP) was observed in Pax6Sey mice starting from post-natal day 20 (P20). Correspondingly, visual acuity showed a steady age-dependent decline in Pax6Sey mice, though these phenotypes were less severe in the 129S1/Svlmj mice. Local retinal damage with layer disorganization was assessed at P30 and P80 in the Pax6Sey mice. Interestingly, we also observed a greater number of activated Iba1+ microglia and GFAP + astrocytes in the Pax6Sey mice than in littermate controls, suggesting a possible neuroinflammatory response to Pax6 deficiencies.

The genetic basis of hypodontia in dental development.

Dental agenesis is one of the most common developmental anomalies in humans, characterised by the developmental absence of one or more teeth. It can present as an isolated condition (non-syndromic hypodontia) or associated with a syndrome (syndromic hypodontia). This paper aims to review the genetic basis of hypodontia with reference to aetiology, classification and the subsequent clinical features.Significant progress has been made to identify the developmental basis of tooth formation, though there is still a lack of knowledge within the literature of the aetiological basis of inherited tooth loss.Gene anomalies or mutations in WNT10A, MSX1, PAX9, AXIN2 and EDA appear to be most critical during tooth development, leading to various forms of tooth agenesis.

THU237 A Case Of Primary Hypothyroidism, Dysglycemia And Epilepsy With PAX8 And SETD1A Mutation

Abstract Disclosure: S.K. Singh: None. KEYWORDS: PAX8, SETD1A, DYSGLYCEMIA INTRODUCTION: Hypothyroidism is associated with dysglycemia linked with insulin resistance and shared common genetic determinants.PAX 8 gene regulates the development of thyroid gland as well as the expression of TG,TPO and NIS genes.It impacts glucose homeostasis by favoring beta-cell survival and through thyroid hormones.Epilepsy in hypothyroid patients can be idiopathic or due to Hashimoto’s Encephalopathy (HE). Thyroid hormones can impact epileptogenesis through mitochondrial dysfunction, oxidative-stress and GABAergic transmission. THE INDEX PATIENT: A 13 year old female(weight and height age 1.5 years below her chronological age by Indian growth chart and a further lag of 18 months and 6 months, respectively by CDC chart)was diagnosed as a case of thyroprivic hypothyroidism with TSH - 100 mIU/L and positive anti-TPO antibody. She was euthyroid on 112 ug/d L-T4.She is on anticonvulsant since 12 years of age for tonic-clonic epilepsy. The MRI of brain showed focal gliosis with few small encephalomalacic streaks in right occipital lobe. On evaluation at 12.5 years of age, her fasting plasma glucose was 80 mg/dl and her HbA1c was 4.8% but 2-h post glucose was 233 mg/dl with another value of 270 mg/dl. Her father has T2DM and Hypothyroidism. Her mother is Hypothyroid. Her genetic study showed SETDIA and PAX8(-) mutations. DISCUSSION: PAX8 regulates development of thyroid gland and biosynthesis of thyroid hormones. It can impact glucose homeostasis by enhancing beta-cell survival by inhibiting apoptosis, immunomodulation, maintaining local anti-inflammatory milieu in pancreas, ensuring systemic levels of thyroid hormone to stimulate insulin secretion and protect beta-cells from environmental stressors.PAX8 mutation in a family has been shown to be associated with a spectrum of disorders encompassing Gestational Thyroid Dysfunction(GTD),Gestational Diabetes Mellitus(GDM) and T2DM.[1] Although mutation analysis was done only in the index patient, Hypothyroidism and Dysglycemia (post- glucose>200 mg/dl)in the patient and family history of Hypothyroidism and T2DM could be linked with PAX8 mutation.SETD1A mutation has been linked with early-onset epilepsy with or without developmental delay. The mutation study can aid in deciding appropriate therapy including steroids for HE. CONCLUSION: This case highlights the significance of evaluation for PAX8 mutation in hypothyroid patients, even if anti-TPO positive, particularly when there is family history of thyroid dysfunction, GDM, T2DM. It also underlies the importance of SETD1A mutation analysis in hypothyroid patients with epilepsy. Presentation: Thursday, June 15, 2023

Mutation of <em>PAX3</em> and <em>MITF</em> genes in a family with type 1 Waardenburg syndrome: a case series

Waardenburg syndrome (WS) is a rare genetical disorder, characterized with pigmentary abnormalities of the eyes, skin, hair, dystopia canthorum, and sensorineural deafness. In Majene, West Sulawesi, 12 members of a 4-generation family presented manifestations of WS. We examined the presence of mutations in 5 family members with type 1 WS and the other 5 normal phenotype family members to identify mutations of PAX3 and MITF genes. Ophthalmic examination and peripheral blood test were done. Conventional polymerase chain reaction and direct Sanger sequencing were then performed to detect the mutation. 26 mutations of PAX3 gene were only identified in patients with major and minor criteria, including 7 missense mutations (substitutions) and 2 insertions in exons 1, 2, and 6, as well as 17 intronic changes in intron 8. No mutations were detected in MITF gene.

A novel microdeletion of 517 kb downstream of the PAX6 gene in a Chinese family with congenital aniridia

BackgroundTo identify the disease-causing gene in a Chinese family affected with congenital aniridia.MethodsPatients underwent systematic ophthalmic examinations such as anterior segment photography, fundus photography, optical coherence tomography, and fundus fluorescein angiography. The proband was screened for pathogenic variants by whole exome sequencing (WES) and copy number variant (CNV) analysis. Real-time quantitative PCR (RT-qPCR) was applied to confirm the CNV results. Breakpoints were identified by long-range PCR followed by Sanger sequencing.ResultsAll seven members of this Chinese family, including four patients and three normal individuals, were recruited for this study. All patients showed bilateral congenital aniridia with nystagmus, except the son of the proband, who presented with bilateral partial coloboma of the iris. A novel heterozygous deletion (chr11:31,139,019–31,655,997) containing the 3’ regulatory enhancers of the PAX6 gene was detected in this family. We also reviewed the reported microdeletions downstream of PAX6 in patients with aniridia.ConclusionsWe identified a novel microdeletion, 517 kb in size located about 133 kb downstream of the PAX6 gene, responsible for congenital aniridia in this Chinese family, which expands the spectrum of aniridia-associated mutations in PAX6.

Two Novel Variants in MITF and PAX3 Associated With Splashed White Phenotypes in Horses.

Mutations causing depigmentation are relatively common in Equus caballus (horse). Over 40 alleles in multiple genes are associated with increased white spotting (as of February 2023). The splashed white phenotype, a coat spotting pattern described as appearing like the horse has been splashed with white paint, was previously associated with variants in the PAX3 and MITF genes. Both genes encode transcription factors known to control melanocyte migration and pigmentation. We report two novel mutations, a stop-gain mutation in PAX3 (XM_005610643.3:c.927C>T, ECA6:11,196,181, EquCab3.0) and a missense mutation in a binding domain of MITF (NM_001163874.1:c.993A>T, ECA16:21,559,940, EquCab3.0), each with a strong association with increased depigmentation in Pura Raza Española horses (P=1.144E-11, N=30, P=4.441E-16, N=39 respectively). Using a quantitative method to score depigmentation, the PAX3 and MITF mutations were found to have average white scores of 25.50 and 24.45, respectively, compared to the average white coat spotting score of 1.89 in the control set. The functional impact for each mutation was predicted to be moderate to extreme (I-TASSER, SMART, Variant Effect Predictor, SIFT). We propose to designate the MITF mutant allele as Splashed White 9 and the PAX3 mutant allele as Splashed White 10 per convention.

Diverse clinical and laboratory phenotypes associated with heterozygous PAX8 mutations

Diverse clinical and laboratory phenotypes associated with heterozygous PAX8 mutations

PAX2 Gene Mutation in Pediatric Renal Disorders-A Narrative Review.

The PAX2 gene is a transcription factor that is essential for the development of the urinary system among other transcription factors. The role of PAX2 is highlighted from the seventh week of gestation, when it is involved in development processes and the emergence of nephrons and collecting tubes. Being an important factor in renal development, mutations of this gene can produce severe alterations in the development of the urinary tract, namely congenital anomalies of the kidneys and urinary tract. The first reported cases described with the PAX2 mutation included both renal anomalies and the involvement of other organs, such as the eyes, producing renal coloboma syndrome. Over the years, numerous cases have been reported, including those with only renal and urinary tract anomalies. The aim of this review is to present a summary of pediatric patients described to have mutations in the PAX2 gene to contribute to a better understanding of the genetic mechanism causing anomalies of the kidneys and urinary tract. In this review, we have included only pediatric cases with renal and urinary tract disorders, without the involvement of other organs. From what we know so far from the literature, this is the first review gathering pediatric patients presenting the PAX2 mutation who have been diagnosed exclusively with renal and urinary tract disorders.

Functional Characteristics of Diverse PAX6 Mutations Associated with Isolated Foveal Hypoplasia.

The human fovea is a specialized pit structure in the central retina. Foveal hypoplasia is a condition where the foveal pit does not fully develop, and it is associated with poor vision. Autosomal dominant isolated foveal hypoplasia (FVH1) is a rare condition of foveal hypoplasia (FH) that lacks any other ocular manifestations. FVH1 is associated with hypomorphic mutations in the PAX6 gene that encodes a sequence-specific DNA-binding transcription factor for morphogenesis and evolution of the eye. We report our findings in 17 patients with PAX6 mutations associated with FVH1 or FH with aniridia and corneal opacities. Patients with three mutations, p.V78E, p.V83F and p.R128H, in the C-terminal subdomain of the paired domain (CTS) consistently have severe FH. Luciferase assays for a single reporter containing a representative PAX6 binding site indicated that the transcriptional activities of these mutations were significantly reduced, comparable to that of the truncation mutation of p.G65Rfs*5. Patients with p.P20S in the N-terminal subdomain of the paired domain, and a patient with p.N365K in the proline-serine-threonine-rich domain (PSTD) had mild FH. A patient with p.Q255L in the homeodomain had severe FH. The P20S and Q255L mutants did not affect the transcriptional activity. Mutant N365K has a retained DNA-binding activity but a reduced transcriptional activity, due to a low PSTD transactivation. These findings demonstrated that mutations associated with FVH1 underlie a functional divergence between DNA-binding ability and transcriptional activity. We conclude that a wide range of mutations in the PAX6 gene is not limited to the CST region and are responsible for FVH1.

Genomic insights into the genetic basis of eagle-beak jaw, large head, and long tail in the big-headed turtle.

The big-headed turtle (Platysternon megacephalum) is an endemic chelonian species in Asia. Unlike most other turtles in the world, P. megacephalum is characterized with eagle-beak jaw, large head, and long tail. Although these unique characteristics are well recognized, the underlying genetic basis remains largely elusive. Here, we performed comparative genomic analysis between P. megacephalum and other representative species, aiming to reveal the genetic basis of the unique morphological features. Our results revealed that the eagle-beak jaw is most likely enabled by combined effects of expansion of SFRP5, extraction of FGF11, and mutation of both ZFYVE16 and PAX6. Large head is supported by mutations of SETD2 and FGRF2 and copy number variations of six head circumference modulation-related genes (TGFBR2, Twist2, Rdh10, Gas1, Chst11, and SNAP25). The long tail is probably involved in a genetic network comprising Gdf11, Lin 28, and HoxC12, two of which showed a consistent expression pattern with a model organism (mice). These findings suggest that expansion, extraction, and mutation of those genes may have profound effects on unique phenotypes of P. megacephalum.

The phenotype and genotype of PAX9 mutations causing tooth agenesis.

The purpose of this study was to identify associations between PAX9 mutations and clinical features of non-syndromic tooth agenesis patients. Non-syndromic tooth agenesis patients were found to have mutations by whole exome sequencing (WES). Additionally, conservation analysis and three-dimensional structure prediction were also applied to identify mutated proteins. Eight non-syndromic tooth agenesis probands were identified with PAX9 mutations (c.C112T; C.131_134del; c.G151A; c.189delG; c.305delT; c.C365A; c.394delG; c.A679C). All of the probands were missing more than six teeth (oligodontia). The mutations (c.131_134del,p.R44fs; c.189delG,p.T63fs; c.305delT,p.I102fs and c.394delG,p.G123fs) caused premature termination of the PAX9 protein. The c.C112T(p.R38X) mutation created a truncated protein. Bioinformatic prediction demonstrated that the three missense mutations change the PAX9 structure suggesting the corresponding functional impairments. We reported that eight mutations of PAX9 caused non-syndromic tooth agenesis and analyzed the relationship between PAX9 mutations and non-syndromic tooth agenesis. Our study revealed that PAX9 mutations might be the mutations most associated with non-syndromic tooth agenesis in humans, which greatly broadened the mutation spectrum of PAX9-related non-syndromic tooth agenesis.

Visual Acuity in Aniridia and WAGR Syndrome.

Our purpose was to evaluate visual acuity in aniridia subjects and the more severely affected phenotype in WAGR syndrome subjects, and to assess potential impact on visual function. This was a retrospective comparative study of 25 aniridia subjects with nonsense mutations of PAX6 (50 eyes) and 25 WAGR syndrome subjects with large deletion mutations involving PAX6 (50 eyes). Aniridia subjects were age- and gender-matched with WAGR syndrome subjects in the Coordination of Rare Diseases at Sanford (CoRDS) database. Best-corrected ETDRS visual acuity measurements were converted to LogMAR visual acuity values, which were used to perform statistical analyses. The age and gender distribution of the subjects was not statistically significantly different. The mean LogMAR values in aniridia and WAGR syndrome subjects were 0.95±0.53 and 1.51±0.99, respectively (P<0.001). In the better-seeing eye, mean LogMAR values were 0.78±0.15 in aniridia subjects and 1.40±0.88 in WAGR syndrome subjects (P=0.001). The mean LogMAR values for the better-seeing eye corresponded to Snellen visual acuity of 20/125 in aniridia subjects and 20/500 in WAGR syndrome subjects. This average visual acuity was worse than the threshold for profound visual impairment (WHO criteria) and legal blindness (AAO criteria) in WAGR syndrome but not in aniridia subjects. In analysis of both eyes, the visual efficiency was 34% in aniridia subjects and 2% in WAGR syndrome subjects. Visual acuity was significantly worse in WAGR subjects with multi-gene deletion mutations compared with aniridia subjects with nonsense mutations, which corresponded to differences in standard visual function thresholds. Our results suggest that visual acuity may indicate severity of ocular involvement and variability of phenotype in aniridia and WAGR syndrome.

PAX9 mutations and genetic synergism in familial tooth agenesis.

Familial tooth agenesis (FTA) is one of the most common craniofacial anomalies in humans. Loss-of-function mutations in PAX9 and WNT10A have been known to cause FTA with various expressivity. In this study, we identified five FTA kindreds with novel PAX9 disease-causing mutations: p.(Glu7Lys), p.(Val83Leu), p.(Pro118Ser), p.(Ser197Argfs*23), and c.771+4A>G. Concomitant PAX9 and WNT10A pathogenic variants found in two probands with severe phenotypes suggested an effect of mutational synergism. All overexpressed PAX9s showed proper nuclear localization, excepting the p.(Pro118Ser) mutant. Various missense mutations caused differential loss of PAX9 transcriptional ability. PAX9 overexpression in dental pulp cells upregulated LEF1 and AXIN2 expression, indicating a positive regulatory role for PAX9 in canonical Wnt signaling. Analyzing 176 cases with 63 different mutations, we observed a distinct pattern of tooth agenesis for PAX9-associated FTA: Maxillary teeth are in general more frequently affected than mandibular ones. Along with all second molars, maxillary bicuspids and first molars are mostly involved, while maxillary lateral incisors and mandibular bicuspids are relatively less affected. Genotypically, missense mutations are associated with fewer missing teeth than frameshift and nonsense variants. This study significantly expands the phenotypic and genotypic spectrums of PAX9-associated disorders and reveals a molecular mechanism of genetic synergism underlying FTA variable expressivity.

Identification of two variants in PAX3 and FBN1 in a Chinese family with Waardenburg and Marfan syndrome via whole exome sequencing

Both Warrensburg (WS) and Marfan syndrome (MFS) can impair the vision. Here, we recruited a Chinese family consisting of two WS affected individuals (II:1 and III:3) and five MFS affected individuals( I:1, II:2, III:1, III:2, and III:5) as well as one suspected MFS individual (II:4). Using whole exome sequencing (WES) and subsequent PCR-Sanger sequencing, we identified one novel heterozygous variant NM_000438 (PAX3) c.208T > C, (p.Cys70Arg) from individuals with WS and one previous reported variant NM_000138 (FBN1) c.2740T > A, (p.Cys914Ser) from individuals with MFS and co-segregated with the diseases. Real-time PCR and Western blot assay showed that, compared to their wild-type,both mRNAs and proteinsof PAX3 and FBN1 mutants reduced in HKE293T cells. Together, our study identified two disease-causing variants in a same Chinese family with WS and MFS, and confirmed their damaged effects on their genes' expression. Therefore, those findings expand the mutation spectrum of PAX3 and provide a new perspective for the potential therapy.

PAX2 and CAKUT Phenotypes: Report on Two New Variants and a Review of Mutations from the Leiden Open Variation Database

PAX2 is a transcription factor expressed during embryogenesis in the eye, ear, CNS, and genitourinary tract, and is one of the major regulators of kidney development. Mutations in this gene are associated with papillorenal syndrome (PAPRS), a genetic condition characterized by optic nerve dysplasia and renal hypo/dysplasia. In the last 28 years, many cohort studies and case reports highlighted PAX2's involvement in a large spectrum of kidney malformations and diseases, with or without eye abnormalities, defining the phenotypes associated with PAX2 variants as "PAX2-related disorders". Here, we reported two new sequence variations and reviewed PAX2 mutations annotated on the Leiden Open Variation Database 3.0. DNA was extracted from the peripheral blood of 53 pediatric patients with congenital abnormalities of the kidney and urinary tract (CAKUT). PAX2 gene-coding exonic and flanking intronic regions were sequenced with Sanger technology. Two unrelated patients and two twins carrying one known and two unknown PAX2 variations were observed. The frequency of PAX2-related disorders in this cohort was 5.8%, considering all CAKUT phenotypes (16.7% in the PAPRS phenotype and 2.5% in non-syndromic CAKUT). Although PAX2 mutations have a higher frequency in patients with PAPRS or non-syndromic renal hypoplasia, from the review of variants reported to date in LOVD3, PAX2-related disorders are detected in pediatric patients with other CAKUT phenotypes. In our study, only one patient had a CAKUT without an ocular phenotype, but his twin had both renal and ocular involvement, confirming the extreme inter- and intrafamilial phenotypic variability.

Novel Mutations of PAX6 and WFS1 Associated With Congenital Cataract in a Chinese Family.

Congenital cataract is a common cause of blindness in childhood. About half of the cases have a genetic etiology, and more than 100 genes have been associated with congenital cataracts. This study reports the clinical and genetic findings of a two-generation Chinese family affected by congenital cataract. Ophthalmologic examinations were performed for clinical evaluation of the cataract patients. Whole exome sequencing (WES) and Sanger sequencing were used to identify potentially relevant mutations. The online programsProtein Variation Effect Analyzer (PROVEAN) and Sorting Intolerant from Tolerant (SIFT) were employed to predict the impact of variation on protein function. Both the proband and her mother were blind because of bilateral nuclear cataracts, and the elder brother of the proband also manifested obvious bilateral cataracts. Sanger sequencing confirmed the mutations in the proband as well as in her mother. The elder brother simply carried the PAX6 c.221G>A variation. The WFS1 c.2070_2079del variation potentially generates a loss-of-function mutant. The novel PAX6mutation (c.221G>A) is associated with congenital cataract, and the WFS1 mutation (c.2070_2079del) may interactively aggravates this process. These findings may increase our understanding of the genetic etiology of congenital cataract.

An inclusive study of deleterious missense PAX9 variants using user-friendly tools reveals structural, functional alterations, as well as potential therapeutic targets.

Mutations in the PAX9 are responsible for non-syndromic tooth agenesis in humans, although their structural and functional consequences on protein phenotype, stability, and posttranslational modifications (PTMs) have not yet been adequately investigated. This in silico study focuses on retrieving the six most deleterious mutations (L21P, R26W, R28P, G51S, I87F, and K91E) of PAX9 that has been linked to severe oligodontia. Several computational algorithm methods were used to determine the deleterious effects of PAX9 mutations. Analysis of gene ontology, protein interactions, and PTMs indicated significant functional changes caused by PAX9 mutations. The structural superimposition of the wild-type and mutant PAX9 variants revealed structural changes in locations that were present in the structures of all six variations. The conserved domain analysis revealed that the areas shared by all six variations contained unique sections that lacked DNA binding or protein-protein interaction sites, suggesting prospective drug target sites for functional restoration. The protein-protein interaction network showed KDM5B as PAX9's strongest interacting partner similar to MSX1. The PAX9 protein's structural conformations, compactness, stiffness, and function may all be impacted by changes, according to MD simulations. In addition, research on cell lines and animal models may be valuable in establishing their specific roles in functional annotations.

New Frameshift in Pax6 And Missense Mutation in Eya1 Gene Found by Whole Exome Sequencing Associated with Severe Eye Impairments in an Iranian Family

Introduction: Previous studies have examined the impacts of PAX6 mutations on a wide range of eye impairments. Because of the PAX6 protein’s binding functions, alterations in its structure may prevent it from correctly connecting with the DNA molecule. 1.2. Materials and Methods: Whole Exome Sequencing [WES] was used to perform in vitro analysis on a 30-year-old woman who sent to a genetic laboratory for PND. Her spouse had clear serious vision problems. To determine the genotypes, both her spouse and her husband’s sister underwent mutation confirmation tests. In silico predictions were also conducted using SWISS-MODEL, ProSA, Molprobity, and SuperPose.

Molecular Genetic Analysis of Ukrainian Families with Congenital Cataracts.

This study was designed to identify the pathogenic variants in five Ukrainian families with autosomal dominant congenital cataracts. Cataracts can be defined broadly as any opacity of the crystalline lens. Lens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes, including the lens crystallins, are associated with congenital cataracts and other eye diseases. Whole-exome sequencing identified heterozygous disease-causing variants in five Ukrainian families with autosomal dominant congenital cataracts and cosegregation with cataracts was confirmed using Sanger sequencing. Family 97001 showed a missense variant (c.341T>A: p.L114Q) in HSF4; family 97003 showed a missense variant (c.53A>T: p.N18I) in CRYGA; family 97004 showed a missense variant (c. 82G>A: p.V28M) in GJA3; family 97006 showed a missense variant (c.83C>T: p. P28L) in CRYGC; and family 97008 showed a single-base insertion resulting in a frameshift (c.443_444insA: p. Met148IfsTer51) in PAX6. All five families are associated with congenital cataracts. Overall, we report four novel mutations in HSF4, CRYGA, CRYGC and PAX6, and one previously reported mutation in GJA3 that cause autosomal dominant congenital cataracts.