Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss.
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Webb BD, Wheeler PG, Hagen JJ, Cohen N, Linderman MD, Diaz GA, Naidich TP, Rodenburg RJ, Houten SM, Schadt EE
Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss.
Hum Mutat. 2015 Jun;36(6):587-92. doi: 10.1002/humu.22781. Epub 2015 Apr 8.
- PubMed ID
- 25754315 [ View in PubMed]
- Abstract
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.