TY - JOUR T1 - Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy JF - Journal of Medical Genetics JO - J Med Genet SP - 151 LP - 159 DO - 10.1136/jmedgenet-2012-101375 VL - 50 IS - 3 AU - Christopher J Carroll AU - Pirjo Isohanni AU - Rosanna Pöyhönen AU - Liliya Euro AU - Uwe Richter AU - Virginia Brilhante AU - Alexandra Götz AU - Taina Lahtinen AU - Anders Paetau AU - Helena Pihko AU - Brendan J Battersby AU - Henna Tyynismaa AU - Anu Suomalainen Y1 - 2013/03/01 UR - http://jmg.bmj.com/content/50/3/151.abstract N2 - Background The genetic complexity of infantile cardiomyopathies is remarkable, and the importance of mitochondrial translation defects as a causative factor is only starting to be recognised. We investigated the genetic basis for infantile onset recessive hypertrophic cardiomyopathy in two siblings. Methods and results Analysis of respiratory chain enzymes revealed a combined deficiency of complexes I and IV in the heart and skeletal muscle. Exome sequencing uncovered a homozygous mutation (L156R) in MRPL44 of both siblings. MRPL44 encodes a protein in the large subunit of the mitochondrial ribosome and is suggested to locate in close proximity to the tunnel exit of the yeast mitochondrial ribosome. We found severely reduced MRPL44 levels in the patient's heart, skeletal muscle and fibroblasts suggesting that the missense mutation affected the protein stability. In patient fibroblasts, decreased MRPL44 affected assembly of the large ribosomal subunit and stability of 16S rRNA leading to complex IV deficiency. Despite this assembly defect, de novo mitochondrial translation was only mildly affected in fibroblasts suggesting that MRPL44 may have a function in the assembly/stability of nascent mitochondrial polypeptides exiting the ribosome. Retroviral expression of wild-type MRPL44 in patient fibroblasts rescued the large ribosome assembly defect and COX deficiency. Conclusions These findings indicate that mitochondrial ribosomal subunit defects can generate tissue-specific manifestations, such as cardiomyopathy. ER -