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X‐linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy
Author(s) -
FernandezMoreira Daniel,
Ugalde Cristina,
Smeets Roel,
Rodenburg Richard J. T.,
LopezLaso Eduardo,
RuizFalco Maria L.,
Briones Paz,
Martin Miguel A.,
Smeitink Jan A. M.,
Arenas Joaquín
Publication year - 2007
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21036
Subject(s) - mitochondrial encephalomyopathy , mitochondrial dna , biology , genetics , gene , mutation , mitochondrial respiratory chain , respiratory chain , phenotype , gene mutation , microbiology and biotechnology , mitochondrion
Objective Mitochondrial complex I deficiency is the commonest diagnosed respiratory chain defect, being genetically heterogeneous. The male preponderance of previous patient cohorts suggested an X‐linked underlying genetic defect. We investigated mutations in the X‐chromosomal complex I structural genes, NDUFA1 and NDUFB11 , as a novel cause of mitochondrial encephalomyopathy. Methods We sequenced 12 nuclear genes and the mitochondrial DNA–encoded complex I genes in 26 patients with respiratory chain complex I defect. Novel mutations were confirmed by polymerase chain reaction restriction length polymorphism. Assembly/stability studies in fibroblasts were performed using two‐dimensional blue native gel electrophoresis. Results Two novel p.Gly8Arg and p.Arg37Ser hemizygous mutations in NDUFA1 were identified in two unrelated male patients presenting with Leigh's syndrome and with myoclonic epilepsy and developmental delay, respectively. Two‐dimensional blue native gel electrophoresis showed decreased levels of intact complex I with no accumulation of lower molecular weight subcomplexes, indicating that assembly, stability, or both are compromised. Interpretation Mutations in the X‐linked NDUFA1 gene result in complex I defect and encephalomyopathy. Assembly/stability analysis might give an explanation for the different clinical phenotypes and become useful for future diagnostic purposes. Ann Neurol 2007;61:73–83