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. 2008 May;82(5):1211-6.
doi: 10.1016/j.ajhg.2008.03.020. Epub 2008 Apr 24.

Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ

Ortal Barel  1 , Zamir Shorer, Hagit Flusser, Rivka Ofir, Ginat Narkis, Gal Finer, Hanah Shalev, Ahmad Nasasra, Ann Saada, Ohad S Birk
Affiliations

Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ

Ortal Barel et al. Am J Hum Genet. 2008 May.

Abstract

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.

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Figures

Figure 1
Figure 1
Pedigree of Affected Israeli-Bedouin Kindred Solid and open symbols represent affected and unaffected individuals, respectively. All affected individuals are offspring of consanguineous marriages. The numbers denote individuals whose DNA samples were analyzed. (A), (B), and (C) are branches of a single extended kindred, remotely related (not first or second degree).
Figure 2
Figure 2
MRI Studies of Affected Individual 133 at Age 2 Years Bilateral symmetrical abnormal findings in the basal ganglia, with increased density in the putamen and decreased density and size of the caudate and globus pallidum nuclei.
Figure 3
Figure 3
Defining the Disease-Associated Locus (A) Partial pedigree of the large Israeli-Bedouin kindred. The affected haplotype is shaded. Physical distances between the markers are shown. (B and C) Fine mapping of the 5q31 locus. In (B), the disease-associated haplotype is boxed. Minimal homozygosity locus associated with the disease is defined between the markers D5S2057 and D5S2497 (gray box). (C) shows a schematic presentation of the defined locus.
Figure 4
Figure 4
Analysis of the C208T Mutation in Exon 2 of UQCRQ Sequence analysis is shown for an affected individual (A), an obligatory carrier (B), and an unaffected individual (C).
See this image and copyright information in PMC

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