Exome sequencing identifies MRPL3 mutation in mitochondrial cardiomyopathy

Abstract

By combining exome sequencing in conjunction with genetic mapping, we have identified the first mutation in large mitochondrial ribosomal protein MRPL3 in a family of four sibs with hypertrophic cardiomyopathy, psychomotor retardation, and multiple respiratory chain deficiency. Affected sibs were compound heterozygotes for a missense MRPL3 mutation (P317R) and a large-scale deletion, inherited from the mother and the father, respectively. These mutations were shown to alter ribosome assembly and cause a mitochondrial translation deficiency in cultured skin fibroblasts resulting in an abnormal assembly of several complexes of the respiratory chain. This observation gives support to the view that exome sequencing combined with genetic mapping is a powerful approach for the identification of new genes of mitochondrial disorders.

Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet

“…Mitochondrial cardiomyopathy has been associated with numerous mutations in both mitochondrial and nuclear DNA-encoded genes (14,(35)(36)(37)(38). Our data indicate that genetic lesions affecting Mediator complex subunits should also be considered as a possible cause of primary cardiomyopathies in humans, particularly in pediatric cases given the importance of MED30 to early cardiac function during the period of weaning in mice.…”

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

“…[4][5][6] Molecular defects that impair different components of the mitochondrial translation machinery can cause combined OXPHOS deficiency. 7 Specifically, 7 of the 80 genes encoding mitochondrial ribosomal proteins have had pathogenic mutations reported, including autosomal-recessive mutations in MRPS7 (MIM: 611974), 8 MRPS16 (MIM: 609204), 9 MRPS22 (MIM: 605810), 10 MRPS23 (MIM: 611985), 11 MRPL3 (MIM: 607118), 12 MRPL12 (MIM: 602375), 13 and MRPL44 (MIM: 611849). 14 Disorders caused by mutations in mitoribosomal proteins are clinically heterogeneous and multi-systemic, with common features including neurodevelopmental disabilities, brain abnormalities, liver disease, kidney disease, cardiomyopathy, and lactic acidosis.…”

Unusual clinical expression and long survival of a pseudouridylate synthase (PUS1) mutation into adulthood

“…7 RESULTS BN-PAGE on cultured skin fibroblasts revealed qualitative anomalies in assembly of complex I respiratory enzyme (Figure 1b), reminiscent of anomalies observed in fibroblasts of patients with mitochondrial translation deficiencies. 8,9 To identify the causative nuclear gene mutation, we sequenced the exome of this patient. From the 22 697 SNPs and Indels identified, the pathogenic variant was selected after filtering against known SNPs reported in dbSNP, 1000 genomes, Exome Variant Server, Intergenic variants and in house polymorphisms.…”