Whole exome sequencing identifies recessive gene as cause of deafness

In a report in the American Journal of Human Genetics, the international consortium of researchers described how whole exome sequencing of three hearing-impaired individuals from three unrelated Pakistani families identified two separate missense mutations in a gene known as KARS, which codes for a protein called lysl-tRNA synthetase, and how they ascertained that these particular gene changes could be damaging. (A missense mutation occurs when a single nucleotide [adenine, cytosine, thymine and guanine] is replaced by another, resulting in production of the wrong amino acid in the protein sequence.)

Recessive disorder

“These are two different missense mutations not reported before,” said Dr. Suzanne Leal, professor of molecular and human genetics at BCM and director of the Center for Statistical Genetics at the College. “We knew the region in which the gene could be found from prior studies, and then we discovered the gene through exome sequencing. We sent one individual from each family for sequencing and in less than an hour after the sequencing was completed, we knew the gene.”

Impaired individuals carry two copies of the mutated gene, making this a recessive disorder. The hearing loss is profound and occurs before the infant begins to speak, Leal said.

Role in sensory hair cells

Using special bioinformatics tools, they could predict that the change in the gene would be deleterious. None of those with the hearing loss have any other deficits or problems that would associated with a syndrome caused by a gene defect. The researchers also sequenced additional people without hearing impairment as comparisons or controls.

In collaboration with researchers at Case Western in Cleveland, they found that the gene is evolutionarily old, playing a role in the sensory hair cells found in chickens, zebra fish and mice. When a gene is conserved across species in that way, it means it is important to an important function.

Leal said first authors Dr. Regie Lyn P. Santos Cortez and Dr. Kwanghyuk Lee played important roles in the study and the collaboration with Dr. Wasim Ahmad of the department of biochemistry at Quaid-i-Azam University in Islamabad, Pakistan, was extremely important.

Others who took part include Paula B. Andrade-Elizondo, Ilene Chiu, both of BCM; Zahid Azeem,, Saadullah Khan, Irfanullah, and Sulman Basit, all of Quaid-i-Azam University in Islamabad; Patrick J. Antonellis, Lana M.Pollock, and Mark D. Adams, at Case Western University in Cleveland, Ohio; and Joshua D. Smith of the University of Washington in Seattle.

Funding for this work came from the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health (NIH) (grants DC03594, DC011651, and DC009437) the National Human Genome Research Institute (grant HG006493) and the Higher Education Commission of Pakistan. Genotyping of the families was performed at the Center for Inherited Disease Research, which is funded through the NIH to The Johns Hopkins University under contract number N01-HG-65403.

Dipali Pathak 713-798-4710

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