RT Journal Article
SR Electronic
T1 Respiratory chain complex I deficiency due to NDUFA12 mutations as a new cause of Leigh syndrome
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 737
OP 740
DO 10.1136/jmg.2011.088856
VO 48
IS 11
A1 Elsebet Ostergaard
A1 Richard J Rodenburg
A1 Mariël van den Brand
A1 Lise Lykke Thomsen
A1 Morten Duno
A1 Mustafa Batbayli
A1 Flemming Wibrand
A1 Leo Nijtmans
YR 2011
UL http://jmg.bmj.com/content/48/11/737.abstract
AB Background This study investigated a girl with Leigh syndrome born to first-cousin parents of Pakistani descent with an isolated respiratory chain complex I deficiency in muscle and fibroblasts. Her early development was delayed, and from age 2 years she started losing motor abilities. Cerebral MRI showed basal ganglia lesions typical of Leigh syndrome.Methods and results A genome-wide search for homozygosity was performed with the Affymetrix GeneChip 50K Xba array. The analysis revealed several homozygous regions. Three candidate genes were identified, and in one of the genes, NDUFA12, a homozygous c.178C→T mutation leading to a premature stop codon (p.Arg60X) was found. Western blot analysis showed absence of NDUFA12 protein in patient fibroblasts and functional complementation by a baculovirus system showed restoration of complex I activity.Conclusion NDUFA12 mutations are apparently not a frequent cause of complex I deficiency, since mutations were not found by screening altogether 122 complex I deficient patients in two different studies. NDUFA12 encodes an accessory subunit of complex I and is a paralogue of NDUFAF2. Despite the complete absence of NDUFA12 protein, a fully assembled and enzymatically active complex I could be found, albeit in reduced amounts. This suggests that NDUFA12 is required either at a late step in the assembly of complex I, or in the stability of complex I.