Autosomal Dominant Posterior Polar Cataract Research Articles

Association of CHMP4B and autophagy with micronuclei: implications for cataract formation.

Autophagy is a mechanism of cellular self-degradation that is very important for cellular homeostasis and differentiation. Components of the endosomal sorting complex required for transport (ESCRT) machinery are required for endosomal sorting and also for autophagy and the completion of cytokinesis. Here we show that the ESCRT-III subunit CHMP4B not only localizes to normal cytokinetic bridges but also to chromosome bridges and micronuclei, the latter surrounded by lysosomes and autophagosomes. Moreover, CHMP4B can be co-immunoprecipitated with chromatin. Interestingly, a CHMP4B mutation associated with autosomal dominant posterior polar cataract abolishes the ability of CHMP4B to localize to micronuclei. We propose that CHMP4B, through its association with chromatin, may participate in the autophagolysosomal degradation of micronuclei and other extranuclear chromatin. This may have implications for DNA degradation during lens cell differentiation, thus potentially protecting lens cells from cataract development.

A new locus in chromosome 2q37-qter is associated with posterior polar cataract

To study the genetic basis of autosomal dominant posterior polar cataracts in two Chinese pedigrees. Peripheral blood samples were collected and genomic DNA was isolated. A genome-wide scan, using microsatellite markers at approximately 10-cm intervals and additional microsatellite markers for the positive region, was performed. Haplotype data were processed using Cyrillic software (version 2.1) to define the region of the disease gene. Mutation analysis was carried out for candidate genes. Sequencing data were analyzed with the software Sequence Scanner v1.0. A maximum two-point LOD score (Z (max)) of 2.53 and 2.03 was obtained at marker D2S125 with recombination θ = 0.00 in the two families. The possible disease genes were located at approximately 8.44-cM between the marker D2S125 and the terminal of chromosome 2q, namely, 2q37-qter. Candidate genes, such as Gamma-crystallins (CRYGA-D), septin 2 (SEPT2), aquaporin 12B (AQP12B), and chemokine orphan receptor 7 (CXCR7), were sequenced but no causative mutations were found. Our results suggest that an unidentified gene in chromosome 2q37-qter is associated with posterior polar cataract, which may have an implication in understanding the genetic and molecular mechanisms of cataracts.

CHMP4B, a Novel Gene for Autosomal Dominant Cataracts Linked to Chromosome 20q

Cataracts are a clinically diverse and genetically heterogeneous disorder of the crystalline lens and a leading cause of visual impairment. Here we report linkage of autosomal dominant "progressive childhood posterior subcapsular" cataracts segregating in a white family to short tandem repeat (STR) markers D20S847 (LOD score [Z] 5.50 at recombination fraction [theta] 0.0) and D20S195 (Z=3.65 at theta =0.0) on 20q, and identify a refined disease interval (rs2057262-(3.8 Mb)-rs1291139) by use of single-nucleotide polymorphism (SNP) markers. Mutation profiling of positional-candidate genes detected a heterozygous transversion (c.386A-->T) in exon 3 of the gene for chromatin modifying protein-4B (CHMP4B) that was predicted to result in the nonconservative substitution of a valine residue for a phylogenetically conserved aspartic acid residue at codon 129 (p.D129V). In addition, we have detected a heterozygous transition (c.481G-->A) in exon 3 of CHMP4B cosegregating with autosomal dominant posterior polar cataracts in a Japanese family that was predicted to result in the missense substitution of lysine for a conserved glutamic acid residue at codon 161 (p.E161K). Transfection studies of cultured cells revealed that a truncated form of recombinant D129V-CHMP4B had a different subcellular distribution than wild type and an increased capacity to inhibit release of virus-like particles from the cell surface, consistent with deleterious gain-of-function effects. These data provide the first evidence that CHMP4B, which encodes a key component of the endosome sorting complex required for the transport-III (ESCRT-III) system of mammalian cells, plays a vital role in the maintenance of lens transparency.

Identification of aCRYABMutation Associated with Autosomal Dominant Posterior Polar Cataract in a Chinese Family

A four-generation Chinese family with 13 members affected with autosomal dominant congenital posterior polar cataract was studied. The purpose of this study was to identify the disease-causing gene in the family and to validate that mutations in CRYAB, the alphaB-crystallin gene, cause the congenital cataract. Linkage analysis was performed with a panel of microsatellite markers flanking candidate genetic loci for cataracts, including 14 known autosomal dominant congenital cataract (ADCC) genes. For mutation analysis, the complete coding region and exon-intron boundaries of CRYAB were sequenced with DNA from the proband. Single-strand conformation polymorphism (SSCP) analysis for exon 1 of CRYAB was performed in all family members and 200 normal control subjects. The disease gene in the Chinese family was mapped to chromosome 11 in region q22-22.3 with a maximum lod score of 4.52. Direct DNA sequence of CRYAB revealed a heterozygous C-->T transition at nucleotide 58, resulting in a novel 58 C-->T (Pro20Ser) mutation. The Pro20Ser mutation cosegregated with all affected individuals and was not present in unaffected members in the family or in 200 normal control subjects. The mutation occurs at the evolutionarily conserved residue Pro20 in the N-terminal region of alphaB-crystallin. To date, only one CRYAB mutation has been associated with congenital isolated cataract. This study identified a second novel mutation in CRYAB in a large Chinese cataract family. Together, these results provide strong evidence that CRYAB is a pathogenic gene for congenital cataract.

Heterozygous and Homozygous Mutations inPITX3in a Large Lebanese Family with Posterior Polar Cataracts and Neurodevelopmental Abnormalities

The PITX3 gene, which codes for a homeobox bicoidlike transcription factor is responsible for dominant cataract and anterior segment mesenchymal dysgenesis in humans. In the current study, a family with autosomal dominant posterior polar cataract (PPC) and a PITX3 mutation that cosegregates with the disease was examined. Also studied were two siblings who were homozygous for the PITX3 mutation who had microphthalmia and significant neurologic impairment. A genome-wide screen, linkage analysis in the PITX3 chromosomal region 10q25, haplotype analysis, and sequencing of the PITX3 gene were performed on 28 affected and 14 unaffected member of a three-generation Lebanese family. Genome-wide linkage analysis showed a lod score of 3.56 at theta = 0.00 on chromosome 10 at area q25. Analysis of the haplotypes and phenotypes confined the disease locus to a region on 10q25 between the markers D10S1239 and D10S1268. A candidate gene, PITX3, maps to that region. Sequencing of the PITX3 gene revealed a heterozygous G deletion mutation in 25 of the 42 family members. In addition, two siblings from a consanguineous marriage were found to be homozygous for the deletion. This is the first report of homozygous PITX3 mutations in humans. The phenotype in these individuals highlights the role of PITX3 in ocular and central nervous system (CNS) development.

Posterior Polar Cataract: Genetic Analysis of a Large Family

Congenital cataracts are clinically and genetically heterogeneous. Loci for autosomal dominant posterior polar cataracts have been mapped to chromosomes 1p36, 11q22-q22.3, 16q22, and 20p12-q12. We investigated a large four-generation family with 20 individuals affected with congenital posterior polar cataracts. After exclusion of known loci for posterior polar cataracts, a genome-wide screen was conducted. In this family, we mapped dominant congenital posterior polar cataracts to chromosome 10q24. On haplotype analysis, we identified an 11-cM interval between loci D10S1680 and D10S467, which included the PITX3 gene. On sequencing the coding region of PITX3, we found a 17-base-pair duplication in exon 4. Although the same genotype was described in a family with ASMD and cataracts, the common phenotype of this mutation is probably posterior polar cataract; a modifier gene is presumed to cause anterior segment abnormalities in the previously described patients. The same mutation was recently identified in four families with congenital cataracts. This study provides further evidence of genetic heterogeneity of autosomal dominant posterior polar cataract.

An autosomal dominant posterior polar cataract locus maps to human chromosome 20p12-q12.

We assigned the locus for a previously reported new type of autosomal dominant posterior polar cataract (CPP3) to 20p12-q12 by a genome-wide two-point linkage analysis with microsatellite markers. CPP3 is characterized by progressive, disc-shaped, posterior subcapsular opacity. The disease was seen in 10 members of a Japanese family and transmitted in an autosomal dominant fashion through four generations. We obtained a maximum lod score (Zmax) of 3.61 with a recombination fraction (theta) of 0.00 for markers D20S917, D20S885 and D20S874. Haplotype analysis gave the disease gene localization at a 15.7-cM interval between D20S851 and D20S96 loci on chromosome 20p12-q12. Since the BFSP1 that encodes the lens-specific beaded filament structural protein 1 (filensin) has been mapped around the CPP3 region, we performed sequence analysis on its entire coding region. However, no base substitution or deletion was detected in the CPP3 patients. The mapping of the CPP3 locus to 20p12-q12 not only expands our understanding of the genetic heterogeneity in autosomal dominant posterior polar cataracts but also is a clue for the positional cloning of the disease gene.

Genetically distinct autosomal dominant posterior polar cataract in a four-generation Japanese family

PURPOSE: To describe the clinical findings of a form of posterior polar cataract in a large Japanese family and to determine whether the posterior polar cataract is causally related to other autosomal dominant cataracts with known genes, chromosomal locations, or both. METHODS: Systemic and ocular histories were obtained and comprehensive ophthalmic examinations were performed in 15 of 37 members of the Japanese family. The posterior polar cataract was transmitted in an autosomal dominant manner through four generations. Although there is some variation in the degree of opacification, the posterior polar cataract in this family is characterized by progressive disk-shaped posterior subcapsular opacities. Genetic linkage analysis was performed with 41 polymorphic microsatellite markers located in chromosomal regions known for linkage to cataracts. Genomic DNA extracted from the 15 individuals was amplified by polymerase chain reaction, the genotype at the marker loci was determined in each family member, and the lod score was calculated at each locus. RESULTS: Significant linkage of the posterior polar cataract was ruled out from the following 10 loci or chromosomal regions: 16q22 and 1p36, to which two forms of autosomal dominant posterior polar cataract have been assigned: 1q21–q25, 2q33–q35, 13cen, 17p13, 17q11–q12, 17q24, 21q22, and 22q, which are the regions responsible for other autosomal dominant congenital cataracts. CONCLUSIONS: This study confirms the genetic heterogeneity of autosomal dominant posterior polar cataracts and demonstrates that the posterior polar cataract in this Japanese family is phenotypically and genetically distinct from previously mapped cataracts.

A locus for autosomal dominant posterior polar cataract on chromosome 1p.

Autosomal dominant congenital cataract is a clinically and genetically heterogeneous lens disease. Here we report the linkage of a locus for autosomal dominant posterior polar cataract (CPP) to the distal short arm of chromosome 1. To map the CPP locus we performed molecular genetic linkage analysis using microsatellite markers in a three-generation pedigree. After exclusion of 13 known loci and candidate lens genes for autosomal dominant cataract, we obtained significantly positive LOD scores for markers D1S508 (Z = 3.14, theta = 0) and D1S468 (Z = 2.71, theta = 0). Multipoint analysis gave a maximum LOD score of 3.48 (theta = 0.07) between markers D1S508 and D1S468. From haplotype data, however, CPP probably lies in the telomeric interval D1S2845-1pter, which includes the locus for the clinically distinct Volkman congenital cataract (CCV). This study provides the first evidence for genetic heterogeneity of autosomal dominant posterior polar cataract for which a locus had been linked previously to chromosome 16q.