Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 5, 1211-1216, 24 April 2008
doi:10.1016/j.ajhg.2008.03.020
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Mitochondrial Complex III Deficiency Associated with a Homozygous Mutation in UQCRQ
Ortal Barel1, Zamir Shorer2, Hagit Flusser2, Rivka Ofir1, Ginat Narkis1, Gal Finer1, Hanah Shalev2, Ahmad Nasasra2, Ann Saada3 and Ohad S. Birk1, 4, 
, 
1 The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva 84105, Israel
2 Division of Pediatrics, Soroka Medical Center, Beer-Sheva 84101, Israel
3 Metabolic Disease Unit, Hadassah Medical Center, Jerusalem 91120, Israel
4 Genetics Institute, Soroka Medical Center, Beer-Sheva 84101, Israel
Corresponding authorAbstract
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 θ = 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.
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