title: POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions.
abstract: The accumulation of multiple mitochondrial DNA (mtDNA) deletions in stable tissues is a distinctive feature of several autosomal disorders, characterized by Progressive External Ophthalmoplegia (PEO), ptosis, and proximal myopathy. At least three nuclear genes are responsible for these disorders: ANT1 and C10orf2 cause autosomal dominant PEO, while mutations of DNA polymerase gammaA (POLG1 or POLG) gene on chromosome 15q25 causes both autosomal dominant and recessive forms of PEO. To investigate the contribution of these genes to the sporadic cases of PEO with multiple mtDNA deletions, we studied 31 mitochondrial myopathy patients without any family history for the disorder: 23 had PEO with myopathy, with or without the additional features of pigmentary retinopathy, ataxia, neurosensorial hypoacusia and diabetes mellitus, 7 presented isolated myopathy and one a peripheral neuropathy with ptosis. In all patients Southern blot of muscle DNA showed multiple mtDNA deletions; screening for ANT1 and C10ORF2 genes was negative. POLG analysis revealed mutations in eight patients; in six of them the mutations were allelic, while two patients were heterozygous. Five mutations were new, namely one stop codon (c.2407C>T/p.R709X) and four missense mutations (c.1085G>C/p.G268A; c.1967G>A/p.R562Q; c.2702G>C/p.R807P; c.3076C>T/p.H932W). A high degree of conservation was observed for all the new missense mutations. Only patients presenting PEO as part of their clinical phenotype had POLG mutations, in seven of them together with myopathic signs and in one with a sensori-motor peripheral neuropathy.
authors.affiliation: Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Università degli Studi di Milano, I.R.C.C.S. Ospedale Maggiore Policlinico and Centro di Eccellenza per le Malattie Neurodegenerative, Milano, Italy. neurogene@policlinico.mi.it
authors.forename: Alessio
authors.initials: A
authors.lastname: Di Fonzo
authors.forename: Andreina
authors.initials: A
authors.lastname: Bordoni
authors.forename: Marco
authors.initials: M
authors.lastname: Crimi
authors.forename: Galbiati
authors.initials: G
authors.lastname: Sara
authors.forename: Roberto
authors.initials: R
authors.lastname: Del Bo
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D018389:Codon, Nonsense; D004247:DNA / Q000737:chemistry / Q000235:genetics; D000074002:DNA Polymerase gamma; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017240:Mitochondrial Myopathies / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
chemical_list: D018389:Codon, Nonsense; D018076:DNA, Complementary; D004272:DNA, Mitochondrial; D004247:DNA; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human