Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82.
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.
Walsh
Tom
T
Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
Shahin
Hashem
H
Elkan-Miller
Tal
T
Lee
Ming K
MK
Thornton
Anne M
AM
Roeb
Wendy
W
Abu Rayyan
Amal
A
Loulus
Suheir
S
Avraham
Karen B
KB
King
Mary-Claire
MC
Kanaan
Moien
M
D000818:Animals; D016764:Cell Polarity; D018389:Codon, Nonsense; D003241:Consanguinity; D047108:Embryonic Development; D018507:Gene Expression Regulation, Developmental; D056726:Genetic Association Studies; D006198:Hair Cells, Auditory / Q000378:metabolism; D034381:Hearing Loss / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation
D018389:Codon, Nonsense; C102754:GPSM2 protein, human; D047908:Intracellular Signaling Peptides and Proteins