Abstract:
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.
journal_name
J Med Genetjournal_title
Journal of medical geneticsauthors
Carroll CJ,Isohanni P,Pöyhönen R,Euro L,Richter U,Brilhante V,Götz A,Lahtinen T,Paetau A,Pihko H,Battersby BJ,Tyynismaa H,Suomalainen Adoi
10.1136/jmedgenet-2012-101375subject
Has Abstractpub_date
2013-03-01 00:00:00pages
151-9issue
3eissn
0022-2593issn
1468-6244pii
jmedgenet-2012-101375journal_volume
50pub_type
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