Functional Characterization of a Novel Loss-of-Function Mutation of PRPS1 related to Early-Onset Progressive Nonsyndromic Hearing Loss in Koreans (DFNX1): Potential Implications on Future Therapeutic Intervention.

Functional Characterization of a Novel Loss-of-Function Mutation of PRPS1 related to Early-Onset Progressive Nonsyndromic Hearing Loss in Koreans (DFNX1): Potential Implications on Future Therapeutic Intervention.

J Gene Med. 2016 Nov 25;:

Authors: Kim SY, Kim AR, Kim NK, Lee C, Han JH, Kim MY, Jeon EH, Park WY, Mittal R, Yan D, Liu XZ, Choi BY

Abstract
BACKGROUND: The symptoms of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) deficiency diseases have been reported to be alleviated by medication. Herein, we report biochemical data to favor PRPS1 deficiency-related hearing loss as a potential target for pharmaceutical treatment.
METHODS: We recruited 42 probands from subjects under the age of 15 years with a moderate degree of nonsyndromic autosomal-recessive or sporadic sensorineural hearing loss (SNHL) in at least one side. Molecular genetic testing, including targeted exome sequencing (TES) of 129 deafness genes, and in silico prediction were performed.
RESULTS: A strong candidate variant-p.A82P-of PRPS1 is co-segregated with SNHL in X-linked recessive inheritance from one Korean multiplex SNHL family. Subsequent measurement of in vitro enzymatic activities of PRPS1 from erythrocytes of affected and unaffected family members as well as unrelated normal controls has confirmed a pathogenic role of this variant. In detail, compared with normal hearing controls (0.23 - 0.26 nmol/ml/h), the proband, affected sibling, and their normal hearing mother demonstrated a significantly decreased PRPS1 enzymatic activity (0.07, 0.03, and 0.11 nmol/ml/h, respectively). This novel loss-of-function mutation of PRPS1-p.A82P-is the 9(th) and 6(th) most reported mutation in the world and in Asia, respectively.
CONCLUSIONS: DFNX1 turned out to account for about 2.4% (1/42) of moderate SNHL in a Korean pediatric population. Confirmation of PRPS1 activity deficiency and an audiologic phenotype that initially begins in a milder form of SNHL, as in our family, should indicate the necessity for rigorous genetic screening as early as possible.

PMID: 27886419 [PubMed - as supplied by publisher]

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