Identification of 51 novel exons of the Usher syndrome type 2A (USH2A) gene that encode multiple conserved functional domains and that are mutated in patients with Usher syndrome type II

Am J Hum Genet. 2004 Apr;74(4):738-44. doi: 10.1086/383096. Epub 2004 Mar 10.


The USH2A gene is mutated in patients with Usher syndrome type IIa, which is the most common subtype of Usher syndrome and is characterized by hearing loss and retinitis pigmentosa. Since mutation analysis by DNA sequencing of exons 1-21 revealed only ~63% of the expected USH2A mutations, we searched for so-far-uncharacterized exons of the gene. We identified 51 novel exons at the 3' end of the gene, and we obtained indications for alternative splicing. The putative protein encoded by the longest open reading frame harbors, in addition to the known functional domains, two laminin G and 28 fibronectin type III repeats, as well as a transmembrane region followed by an intracellular domain with a PDZ-binding domain at its C-terminal end. Semiquantitative expression profile analysis suggested a low level of expression for both the long and the short isoform(s) and partial overlap in spatial and temporal expression patterns. Mutation analysis in 12 unrelated patients with Usher syndrome, each with one mutation in exons 1-21, revealed three different truncating mutations in four patients and two missense mutations in one patient. The presence of pathogenic mutations in the novel exons indicates that at least one of the putative long isoforms of the USH2A protein plays a role in both hearing and vision.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Amino Acid Sequence
  • Base Sequence
  • Conserved Sequence / genetics*
  • DNA Mutational Analysis
  • Exons / genetics*
  • Extracellular Matrix Proteins / chemistry
  • Extracellular Matrix Proteins / genetics*
  • Hearing Loss, Sensorineural / genetics*
  • Humans
  • Introns / genetics
  • Molecular Sequence Data
  • Mutation / genetics*
  • Open Reading Frames / genetics
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Structure, Tertiary
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Retinitis Pigmentosa / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction


  • Extracellular Matrix Proteins
  • Protein Isoforms
  • RNA, Messenger
  • USH2A protein, human

Associated data

  • GENBANK/AK044734
  • GENBANK/AY481573
  • OMIM/276901
  • RefSeq/NM_007123