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

Abstract

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.

Congenital dyserythropoietic anemia type II (CDAII) is caused by mutations in theSEC23Bgene

“…The CHMP4B, AHCY, and GSS genes were a priori excluded because they are known to be associated with autosomal dominant cataracts, S-adenosylhomocysteine hydrolase deficiency, and glutathione synthetase deficiency, respectively [Shiels et al, 2007;Baric et al, 2004;Shi et al, 1996]. Moreover, EIF6 and EPB41L1 were not considered because they have already been investigated in CDAII [Lanzara et al, 2003].…”

Rapid and cost-effective molecular diagnosis using exome sequencing of one proband with autosomal dominant congenital cataract

“…edu/fannsdb/). A total of 18 previously reported ADCC disease-causing genes were selected to analyze: night crystallin genes, including aA-crystallin (CRYAA), 9 aB-crystallin (CRYAB), 10 bA1-crystallin (CRYBA1), 11 bA4-crystallin (CRYBA4), 12 bB1-crystallin (CRYBB1), 13 bB2-crystallin (CRYBB2), 14 gC-crystallin (CRYGC), 15 gD-crystallin (CRYGD), 16 and gS-crystallin (CRYGS); 17 one cytoskeletal protein gene: beaded filament structural protein 2 (BFSP2); 18 three membrane protein genes: gap junction protein alpha 3 (GJA3), 19 gap junction protein alpha 8 (GJA8), 20 and major intrinsic protein of lens fiber (MIP); 21 three growth and transcription factor genes, including heat-shock transcription factor 4 (HSF4), 22 paired-like homeodomain 3 (PITX3), 23 and v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF); 24 and two other genes, including chromatin modifying protein-4B (CHMP4B), 25 and Ephrin receptor A2 (EPHA2). 26 For splice site variants, indels, and nonsynomymous SNVs predicted to be functionally deleterious, a comprehensive literature search was conducted to identify known disease-causing variants of ADCC.…”

Etiology and Prevention of Cataract

“…At least 34 loci in the human genome have been reported to be associated with various forms of pediatric cataract. Autosomal dominant and recessive forms of cataracts have been caused by mutations in 22 different genes encoding crystallins CRYAA [ 40 ], CRYAB [ 41 ], CRYBA1 [ 42 ], CRYBA4 [ 43 ], CRYBB1 [ 44 ], CRYBB2 [ 45 ], CRYBB3 [ 46 ], CRYGC, CRYGD [ 47 ], and CRYGS [ 48 ], cytoskeletal proteins BFSP1 [ 49 ] and BFSP2 [ 50 ], membrane proteins GJA3 [ 51 ] and GJA8 [ 52 ], MIP [ 53 ] and LIM2 [ 54 ], transcription factors HSF4 [ 55 ], PITX3 [ 56 ], and MAF [ 57 ], glucosaminyl ( N -acetyl) transferase 2 (GCNT2) [ 58 ], chromatin modifying protein-4B CHMP4B [ 59 ] and TMEM114 [ 60 ] (Table 16.2 ). On the basis of current studies, mutations in about half of the affected families occurs in crystallin gene, a quarter in connexins and the remaining is evenly split between membrane proteins, intermediate fi lament proteins, and transcription factors.…”