title: Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.
abstract: Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding of the recurrence risks. Mutations were identified in 38 cases, with the majority being sporadic compound heterozygotes. Eighty-nine DNA sequence changes were identified, including 2 predicted to alter a splice site, 1 predicted to cause a premature stop codon and 13 predicted to cause novel amino acid substitutions. The majority of children had a mutation in the linker region, often 1399G-->A (A467T), and a mutation affecting the polymerase domain. Others had mutations throughout the gene, and 11 had 3 or more substitutions. The clinical presentation ranged from the neonatal period to late adult life, with an overlapping phenotypic spectrum from severe encephalopathy and liver failure to late-onset external ophthalmoplegia, ataxia, myopathy and isolated muscle pain or epilepsy. There was a strong gender bias in children, with evidence of an environmental interaction with sodium valproate. POLG1 mutations cause an overlapping clinical spectrum of disease with both dominant and recessive modes of inheritance. 1399G-->A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.
authors.affiliation: Metabolic Diseases Centre, Munich-Schwabing, Institutes of Clinical Chemistry, Molecular Diagnostics and Mitochondrial Genetics, Academic Hospital Schwabing Munich, Germany.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.forename: Gavin
authors.initials: G
authors.lastname: Hudson
authors.forename: Gianfrancesco
authors.initials: G
authors.lastname: Ferrari
authors.forename: Nancy
authors.initials: N
authors.lastname: Fütterer
authors.forename: Sofia
authors.initials: S
authors.lastname: Ahola
authors.forename: Eleonora
authors.initials: E
authors.lastname: Lamantea
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Robert
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authors.lastname: McFarland
authors.forename: V
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authors.lastname: Ramesh
authors.forename: Thomas
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authors.lastname: Klopstock
authors.forename: Peter
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authors.lastname: Freisinger
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Salvi
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.forename: Rene
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authors.lastname: Santer
authors.forename: Marketa
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authors.lastname: Tesarova
authors.forename: Jiri
authors.initials: J
authors.lastname: Zeman
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Douglass
authors.initials: D
authors.lastname: Turnbull
authors.forename: Michael
authors.initials: M
authors.lastname: Hanna
authors.forename: Doreen
authors.initials: D
authors.lastname: Fialho
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000235:genetics*; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics; D009154:Mutation; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics; D010641:Phenotype; D012737:Sex Factors
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human