Mutation in mitochondrial ribosomal protein MRPS22 leads to Cornelia de Lange-like phenotype, brain abnormalities and hypertrophic cardiomyopathy

Abstract

The oxidative phosphorylation (OXPHOS) system is under control of both the mitochondrial and the nuclear genomes; 13 subunits are synthesized by the mitochondrial translation machinery. We report a patient with Cornelia de Lange-like dysmorphic features, brain abnormalities and hypertrophic cardiomyopathy, and studied the genetic defect responsible for the combined OXPHOS complex I, III and IV deficiency observed in fibroblasts. The combination of deficiencies suggested a primary defect associated with the synthesis of mitochondrially encoded OXPHOS subunits. Analysis of mitochondrial protein synthesis revealed a marked impairment in mitochondrial translation. Homozygosity mapping and sequence analysis of candidate genes revealed a homozygous mutation in MRPS22, a gene encoding a mitochondrial ribosomal small subunit protein. The mutation predicts a Leu215Pro substitution at an evolutionary conserved site. Mutations in genes implicated in Cornelia de Lange syndrome or copy number variations were not found. Transfection of patient fibroblasts, in which MRPS22 was undetectable, with the wild-type MRPS22 cDNA restored the amount and activity of OXPHOS complex IV, as well as the 12S rRNA transcript level to normal values. These findings demonstrate the pathogenicity of the MRPS22 mutation and stress the significance of mutations in nuclear genes, including genes that have no counterparts in lower species like bacteria and yeast, for mitochondrial translation defects.

Exome sequencing identifies MRPL3 mutation in mitochondrial cardiomyopathy

“…Abnormal assembly of RC in translation deficiency has been documented in GFM1 Coenen et al, 2004], TSFM [Smeitink et al, 2006], C12orf65 [Antonicka et al, 2010], and MRPS22 [Smits et al, 2011] mutations. Unfortunately, RC assembly has not been studied in patients with MRPS16, PUS1, RARS2, YARS2, and TRMU mutations.…”

Cardiomyopathy Is Associated with Ribosomal Protein Gene Haplo-Insufficiency inDrosophila melanogaster

“…In addition, several human MRP genes map to loci associated with disorders consistent with impaired oxidative phosphorylation (O'Brien et al 2005). Mutations of human MRPS22 and MRP16 have been shown to cause severe disease in the homozygous state (Miller et al 2004;Saada et al 2007;Smits et al 2010), showing that complete lack of a MRP is extremely detrimental. Future investigation of human ribosomal protein gene mutations, both in the heterozygous and homozygous states, may reveal insights into ribosomal biology and cardiovascular disease.…”

The effect of small molecules on nuclear-encoded translation diseases

“…Four patients have received molecular diagnosis of mutations in the gene encoding the ribosomal protein MRPS22 [24,25] and 12 patients in TRMU, which encodes a protein responsible for 2-thiouridylation of mitochondrial tRNAs [5,26,27].…”