RT Journal Article
SR Electronic
T1 Mitochondrial DNA polymerase γ mutations: an ever expanding molecular and clinical spectrum
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 669
OP 681
DO 10.1136/jmedgenet-2011-100222
VO 48
IS 10
A1 Sha Tang
A1 Jing Wang
A1 Ni-Chung Lee
A1 Margherita Milone
A1 Michelle C Halberg
A1 Eric S Schmitt
A1 William J Craigen
A1 Wei Zhang
A1 Lee-Jun C Wong
YR 2011
UL http://jmg.bmj.com/content/48/10/669.abstract
AB Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial diseases in children and adults. This study sequenced the exons and flanking intronic regions of the POLG gene from 2697 unrelated patients with clinical presentations suggestive of POLG deficiency. Informative mutations have been identified in 136 unrelated individuals (5%), including 92 patients with two recessive pathogenic alleles and three patients harbouring a dominant mutation. Twenty-four novel recessive mutations and a novel possible dominant mutation, p.Y951N, were identified. All missense mutations occurred at evolutionarily conserved amino acids within functionally important regions identified by molecular modelling analyses. Oligonucleotide array comparative genomic hybridisation analyses performed on DNA samples from 81 patients with one mutant POLG allele identified a large intragenic deletion in only one patient, suggesting that large deletions in POLG are rare. The 92 patients with two mutant alleles exhibited a broad spectrum of disease. Almost all patients in all age groups had some degree of neuropathy. Seizures, hepatopathy, and lactic acidaemia were predominant in younger patients. By comparison, patients who developed symptoms in adulthood had a higher percentage of myopathy, sensory ataxia, and chronic progressive external ophthalmoplegia (CPEO)/ptosis. In conclusion, POLG mutations account for a broad clinical spectrum of mitochondrial disorders. Sequence analysis of the POLG gene should be considered as a part of routine screening for mitochondrial disorders, even in the absence of apparent mitochondrial DNA abnormalities.