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NIDCD-supported researchers discover mutations associated with Perrault syndrome, a rare hereditary form of deafness and ovarian failure
An international team of researchers partially supported by funding from the National Institute on Deafness and Other Communication Disorders (NIDCD), a component of the National Institutes of Health (NIH), has identified three genetic variants associated with a rare form of sensorineural hearing loss known as Perrault syndrome. The mutations, found in the CLPP gene, interfere with protein regulation essential to the normal function of mitochondria—cellular structures that operate as energy generators in cells. The findings appear in the March 28, 2013 online edition of the American Journal of Human Genetics and will be published in the journal’s April issue. The co-lead authors of the study are Emma M. Jenkinson, Ph.D., at the Centre for Genetic Medicine, University of Manchester and Atteeq U. Rehman, Ph.D., in the Laboratory of Molecular Genetics at the NIDCD.
Perrault syndrome is a rare autosomal recessive condition characterized by moderate to severe sensorineural hearing loss at birth in both males and females. In females, the hearing loss is accompanied by ovarian failure and infertility, which often isn’t noticed until puberty or child-bearing years. Sensorineural hearing loss is caused by disorders of the inner ear or auditory nerve.
Mutations in two genes (HSD17B4 and HARS2) had previously been identified as underlying causes of Perrault syndrome, but these mutations couldn’t account for all cases of the syndrome.
The researchers used genetic mapping and next generation sequencing techniques on genetic material gathered from three unrelated Pakistani families some of whose children had profound deafness at birth and other symptoms associated with Perrault syndrome, such as muscular incoordination, spasticity, and learning difficulties. The researchers narrowed the search within a critical region on chromosome 19p13, and further studies revealed novel genetic variants in only one gene, CLPP, in all three families.
The protein made by the CLPP gene appears to play the role of a kind of cellular vacuum cleaner, sucking up misfolded proteins that could potentially clog the precise cellular machinery of mitochondria. Most likely, the mutations found in CLPP disable the protein and keep it from doing its job. This allows misfolded proteins to build up within the cell and interfere with normal cellular function. Previous identification of variations in the HARS2 gene had also pointed to an association with the disruption of mitochondrial function as a cause of Perrault syndrome.
“The study is important,” says Andrew Griffith, M.D., Ph.D., scientific director of the NIDCD, “because mutations in the Perrault syndrome genes may account for a larger proportion of cases of childhood hearing loss than we have previously suspected. Clinicians should be aware that some cases of moderate to severe deafness at birth might be part of a larger complex of symptoms related to a hereditary deafness syndrome.”
The research was supported by NIDCD intramural funds (DC00039) to Thomas B. Friedman, Ph.D., Chief, Section on Human Genetics, Laboratory of Molecular Genetics at the NIDCD, who collaborated with William G. Newman, M.D., Ph.D. at the Centre for Genetic Medicine, University of Manchester, and Sheikh Riazuddin, Ph.D., at the Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan. Additional NIDCD funding (DC011651, DC03594) supported a co-author of this study, Mary-Claire King, Ph.D. at the University of Washington and Suzanne M. Leal, Ph.D. at the Baylor College of Medicine.