Congenital myopathy is caused by mutation of HACD1.
Congenital myopathies are heterogeneous inherited diseases of muscle characterized by a range of distinctive histologic abnormalities. We have studied a consanguineous family with congenital myopathy. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous non-sense mutation in 3-hydroxyacyl-CoA dehydratase 1 (HACD1) in affected individuals. The mutation results in non-sense mediated decay of the HACD1 mRNA to 31% of control levels in patient muscle and completely abrogates the enzymatic activity of dehydration of 3-hydroxyacyl-CoA, the third step in the elongation of very long-chain fatty acids (VLCFAs). We describe clinical findings correlated with a deleterious mutation in a gene not previously known to be associated with congenital myopathy in humans. We suggest that the mutation in the HACD1 gene causes a reduction in the synthesis of VLCFAs, which are components of membrane lipids and participants in physiological processes, leading to congenital myopathy. These data indicate that HACD1 is necessary for muscle function.
Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences and.
Emad
E
Muhammad
Orit
O
Reish
Yusuke
Y
Ohno
Todd
T
Scheetz
Adam
A
Deluca
Charles
C
Searby
Miriam
M
Regev
Lilach
L
Benyamini
Yakov
Y
Fellig
Akio
A
Kihara
Val C
VC
Sheffield
Ruti
R
Parvari
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D059472:Exome / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D008040:Genetic Linkage; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D009135:Muscular Diseases / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D020871:RNA Stability / Q000235:genetics*
D005227:Fatty Acids; C404489:HACD1 protein, human; D017027:Protein Tyrosine Phosphatases