Mutations in mitochondrial ribosomal protein MRPL12 leads to growth retardation, neurological deterioration and mitochondrial translation deficiency

Abstract

Multiple respiratory chain deficiencies represent a common cause of mitochondrial diseases and are associated with a wide range of clinical symptoms. We report a subject, born to consanguineous parents, with growth retardation and neurological deterioration. Multiple respiratory chain deficiency was found in muscle and fibroblasts of the subject as well as abnormal assembly of complexes I and IV. A microsatellite genotyping of the family members detected only one region of homozygosity on chromosome 17q24.2–q25.3 in which we focused our attention to genes involved in mitochondrial translation. We sequenced MRPL12, encoding the mitochondrial ribosomal protein L12 and identified a c.542C>T transition in exon 5 changing a highly conserved alanine into a valine (p.Ala181Val). This mutation resulted in a decreased steady-state level of MRPL12 protein, with altered integration into the large ribosomal subunit. Moreover, an overall mitochondrial translation defect was observed in the subject's fibroblasts with a significant reduction of synthesis of COXI, COXII and COXIII subunits. Modeling of MRPL12 shows Ala181 positioned in a helix potentially involved in an interface of interaction suggesting that the p.Ala181Val change might be predicted to alter interactions with the elongation factors. These results contrast with the eubacterial orthologues of human MRPL12, where L7/L12 proteins do not appear to have a selective effect on translation. Therefore, analysis of the mutated version found in the subject presented here suggests that the mammalian protein does not function in an entirely analogous manner to the eubacterial L7/L12 equivalent.

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.…”

Mitochondrial ribosome assembly in health and disease

“…MRPL3 mutations were identified in four siblings of the same family presenting cardiomyopathy and psychomotor retardation [210]. A homozygous MRPL12 mutation was associated with growth retardation and neurological deterioration in a single patient born to consanguineous parents [211]. Finally, a homozygous MRPL44 mutation was identified in two siblings suffering from recessive hypertrophic cardiomyopathy [212].…”

Mitochondrial Ribosomal Protein L12 Is Required for POLRMT Stability and Exists as Two Forms Generated by Alternative Proteolysis during Import

“…Splicing-Two forms of MRPL12 have been observed by Western blot in previous studies (16,21). However, because there is some variability within and between studies, it is not clear if these are conserved and reproducible.…”

“…In mammalian mitochondria, MRPL12 dimers are bound to the ribosome (20). We and others have observed two forms of mammalian MRPL12 in Western blots, which appear to differ in size by more that can be accounted for by the presence and absence of N-terminal acety-lation (16,21). In this report, we investigated how these two forms of human MRPL12 are generated and whether they have different functional properties.…”