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A novel mitochondrial DNA m.7507A > G mutation is only pathogenic at high levels of heteroplasmy

Lookup NU author(s): Dr Helen Tuppen, Professor Robert Taylor


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We present a Dutch family with a novel disease-causing mutation in the mitochondrial tRNA(Ser(UCN)) gene, m.7507A>G. The index patient died during the neonatal period due to cardio respiratory failure and fatal lactic acidosis. A second patient, his cousin, has severe hearing loss necessitating cochlear implants and progressive exercise intolerance. Laboratory investigations of both patients revealed combined deficiencies of the enzyme complexes of the mitochondrial respiratory chain in several tissues. Reduced levels of fully assembled complexes I and IV in fibroblasts by BN-PAGE associated with (near) homoplasmic levels of the m.7507A>G mutation in several tissues and a severe reduction in the steady-state level of mt-tRNA(Ser(UCN)) in fibroblasts were observed. The novel mitochondrial DNA mutation was shown to segregate with disease; several healthy maternal family members showed high heteroplasmy levels (up to 76 +/- 4% in blood and 68 +/- 4% in fibroblasts) which did not lead to any alterations in the activities of the enzyme complexes of the respiratory chain in fibroblasts or clinical signs and symptoms. We hereby conclude that the m.7507A>G mutation causes a heterogeneous clinical phenotype and is only pathogenic at very high levels of mtDNA heteroplasmy. (C) 2014 Elsevier B.V. All rights reserved.

Publication metadata

Author(s): McCann BJ, Tuppen HAL, Kusters B, Lammens M, Smeitink JAM, Taylor RW, Rodenburg RJ, Wortmann SB

Publication type: Article

Publication status: Published

Journal: Neuromuscular Disorders

Year: 2015

Volume: 25

Issue: 3

Pages: 262-267

Print publication date: 01/03/2015

Online publication date: 12/11/2014

Acceptance date: 06/11/2014

ISSN (print): 0960-8966

ISSN (electronic): 1873-2364

Publisher: Elsevier


DOI: 10.1016/j.nmd.2014.11.002


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Funder referenceFunder name
UK NHS Highly Specialised "Rare Mitochondrial Disorders of Adults and Children" Service
096919Z/11/ZWellcome Trust