Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss

Summary

Novel, single-nucleotide mutations were identified in the mitochondrial methionyl amino-acyl tRNA synthetase gene (MARS2) via whole exome sequencing in two affected siblings with developmental delay, poor growth, and sensorineural hearing loss.We show that compound heterozygous mutations c.550C>T:p.Gln 184* and c.424C>T:p.Arg142Trp in MARS2 lead to decreased MARS2 protein levels in patient lymphoblasts. Analysis of respiratory complex enzyme activities in patient fibroblasts revealed decreased complex I and IV activities. Immunoblotting of patient fibroblast and lymphoblast samples revealed reduced protein levels of NDUFB8 and COXII, representing complex I and IV, respectively. Additionally, overexpression of wild-type MARS2 in patient fibroblasts increased NDUFB8 and COXII protein levels. These findings suggest that recessive single-nucleotide mutations in MARS2 are causative for a new mitochondrial translation deficiency disorder with a primary phenotype including developmental delay and hypotonia. Identification of additional patients with single-nucleotide mutations in MARS2 is necessary to determine if pectus carinatum is also a consistent feature of this syndrome. © 2015 WILEY PERIODICALS, INC.

Authors	Webb BD, Wheeler PG, Hagen JJ, Cohen N, Linderman MD, Diaz GA, Naidich TP, Rodenburg RJ, Houten SM, Schadt EE
Journal	Human mutation
Publication Date	2015 Jun;36(6):587-92
PubMed	25754315
PubMed Central	PMC4439286
DOI	10.1002/humu.22781

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