Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82

Am J Hum Genet. 2010 Jul 9;87(1):90-4. doi: 10.1016/j.ajhg.2010.05.010. Epub 2010 Jun 17.


Massively parallel sequencing of targeted regions, exomes, and complete genomes has begun to dramatically increase the pace of discovery of genes responsible for human disorders. Here we describe how exome sequencing in conjunction with homozygosity mapping led to rapid identification of the causative allele for nonsyndromic hearing loss DFNB82 in a consanguineous Palestinian family. After filtering out worldwide and population-specific polymorphisms from the whole exome sequence, only a single deleterious mutation remained in the homozygous region linked to DFNB82. The nonsense mutation leads to an early truncation of the G protein signaling modulator GPSM2, a protein that is essential for maintenance of cell polarity and spindle orientation. In the mouse inner ear, GPSM2 is localized to apical surfaces of hair cells and supporting cells and is most highly expressed during embryonic development. Identification of GPSM2 as essential to the development of normal hearing suggests dysregulation of cell polarity as a mechanism underlying hearing loss.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Polarity
  • Codon, Nonsense
  • Consanguinity
  • Embryonic Development
  • Gene Expression Regulation, Developmental
  • Genetic Association Studies
  • Hair Cells, Auditory / metabolism
  • Hearing Loss / genetics*
  • Homozygote
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mutation


  • Codon, Nonsense
  • GPSM2 protein, human
  • Intracellular Signaling Peptides and Proteins