CHMP4B, a novel gene for autosomal dominant cataracts linked to chromosome 20q

Am J Hum Genet. 2007 Sep;81(3):596-606. doi: 10.1086/519980. Epub 2007 Jul 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics*
  • Cataract / genetics*
  • Cataract / pathology
  • Chromosomes, Human, Pair 20 / genetics*
  • Endosomal Sorting Complexes Required for Transport
  • Genes, Dominant*
  • Genetic Linkage
  • Glutamic Acid / chemistry
  • Glutamic Acid / genetics
  • Humans
  • Lens, Crystalline / pathology
  • Lod Score
  • Lysine / chemistry
  • Lysine / genetics
  • Molecular Sequence Data
  • Mutation, Missense
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Transfection


  • CHMP4B protein, human
  • Carrier Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Glutamic Acid
  • Lysine