title: Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum.
abstract: 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.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Sha
authors: S
authors: Tang
authors: Jing
authors: J
authors: Wang
authors: Ni-Chung
authors: NC
authors: Lee
authors: Margherita
authors: M
authors: Milone
authors: Michelle C
authors: MC
authors: Halberg
authors: Eric S
authors: ES
authors: Schmitt
authors: William J
authors: WJ
authors: Craigen
authors: Wei
authors: W
authors: Zhang
authors: Lee-Jun C
authors: LJ
authors: Wong
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000151:congenital / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D008958:Models, Molecular; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results
chemical_list: D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human