title: 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.
authors: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA. shiels@vision.wustl.edu
authors: Alan
authors: A
authors: Shiels
authors: Thomas M
authors: TM
authors: Bennett
authors: Harry L S
authors: HL
authors: Knopf
authors: Koki
authors: K
authors: Yamada
authors: Koh-ichiro
authors: K
authors: Yoshiura
authors: Norio
authors: N
authors: Niikawa
authors: Soomin
authors: S
authors: Shim
authors: Phyllis I
authors: PI
authors: Hanson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D002386:Cataract / Q000235:genetics* / Q000473:pathology; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D056827:Endosomal Sorting Complexes Required for Transport; D005799:Genes, Dominant; D008040:Genetic Linkage; D018698:Glutamic Acid / Q000737:chemistry / Q000235:genetics; D006801:Humans; D007908:Lens, Crystalline / Q000473:pathology; D008126:Lod Score; D008239:Lysine / Q000737:chemistry / Q000235:genetics; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D014162:Transfection
chemical_list: C478397:CHMP4B protein, human; D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D018698:Glutamic Acid; D008239:Lysine
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