Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ.
A consanguineous Israeli Bedouin kindred presented with an autosomal-recessive nonlethal phenotype of severe psychomotor retardation and extrapyramidal signs, dystonia, athetosis and ataxia, mild axial hypotonia, and marked global dementia with defects in verbal and expressive communication skills. Metabolic workup was normal except for mildly elevated blood lactate levels. Brain magnetic resonance imaging (MRI) showed increased density in the putamen, with decreased density and size of the caudate and lentiform nuclei. Reduced activity specifically of mitochondrial complex III and variable decrease in complex I activity were evident in muscle biopsies. Homozygosity of affected individuals to UQCRB and to BCSIL, previously associated with isolated complex III deficiency, was ruled out. Genome-wide linkage analysis identified a homozygosity locus of approximately 9 cM on chromosome 5q31 that was further narrowed down to 2.14 cM, harboring 30 genes (logarithm of the odds [LOD] score 8.82 at theta = 0). All 30 genes were sequenced, revealing a single missense (p.Ser45Phe) mutation in UQCRQ (encoding ubiquinol-cytochrome c reductase, complex III subunit VII, 9.5 kDa), one of the ten nuclear genes encoding proteins of mitochondrial complex III.
Barel
Ortal
O
The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva 84105, Israel.
Shorer
Zamir
Z
Flusser
Hagit
H
Ofir
Rivka
R
Narkis
Ginat
G
Finer
Gal
G
Shalev
Hanah
H
Nasasra
Ahmad
A
Saada
Ann
A
Birk
Ohad S
OS
D002675:Child, Preschool; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D003241:Consanguinity; D014450:Electron Transport Complex III / Q000172:deficiency* / Q000235:genetics*; D008040:Genetic Linkage; D015894:Genome, Human; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D009154:Mutation; D010375:Pedigree
D014450:Electron Transport Complex III