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Hum Mol Genet. 2015 Apr 15;24(8):2297-307. doi: 10.1093/hmg/ddu747. Epub 2015 Jan 2.

Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia.

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Genetic Metabolic Disorders Research Unit, Discipline of Paediatrics and Child Health and.
The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
T-Life Research Center, Fudan University, Shanghai 200433, China, BGI-Shenzhen, Shenzhen 518083, China.
Institute for Neuroscience and Muscle Research, Discipline of Paediatrics and Child Health and.
Murdoch Children's Research Institute and Victorian Clinical Genetics Services, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, VIC 3052, Australia, Department of Paediatrics, University of Melbourne, Melbourne, VIC 3010, Australia.
BGI-Shenzhen, Shenzhen 518083, China.
Department of Chemistry and Biochemistry, University of Sciences, Philadelphia, PA, USA.
Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney, Australia.
Centre for Kidney Research and Discipline of Paediatrics and Child Health and.
Histopathology Department, Children's Hospital at Westmead 2145, Sydney, Australia.
Electron Microscopy Unit, Department of Anatomical Pathology, Concord Repatriation General Hospital, Concord, Sydney, Australia.
The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA, Department of Pediatrics and Department of Human Genetics, The Perelmen School of Medicine, University of Pennsylvania, Philadelphia, PA, USA and.
Genetic Metabolic Disorders Research Unit, Discipline of Paediatrics and Child Health and Discipline of Genetic Medicine, University of Sydney, Sydney, NSW 2006, Australia,


Functional defects of the mitochondrial translation machinery, as a result of mutations in nuclear-encoded genes, have been associated with combined oxidative phosphorylation (OXPHOS) deficiencies. We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver. One of the siblings had a more severe phenotype showing progressive hepatic and renal failure. Whole-exome sequencing revealed a homozygous mutation in the gene encoding mitochondrial ribosomal protein S7 (MRPS7), a c.550A>G transition that encodes a substitution of valine for a highly conserved methionine (p.Met184Val) in both affected siblings. MRPS7 is a 12S ribosomal RNA-binding subunit of the small mitochondrial ribosomal subunit, and is required for the assembly of the small ribosomal subunit. Pulse labeling of mitochondrial protein synthesis products revealed impaired mitochondrial protein synthesis in patient fibroblasts. Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function. Moreover, reduced 12S rRNA transcript levels observed in the patient's fibroblasts were also restored to normal levels by exogenous expression of wild-type MRPS7. Our data demonstrate the pathogenicity of the identified MRPS7 mutation as a novel cause of mitochondrial RC dysfunction, congenital sensorineural deafness and progressive hepatic and renal failure.

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