title: What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr?
abstract: Polymerase-γ (POLG) is a major human disease gene and may account for up to 25% of all mitochondrial diseases in the UK and in Italy. To date, >150 different pathogenic mutations have been described in POLG. Some mutations behave as both dominant and recessive alleles, but an autosomal recessive inheritance pattern is much more common. The most frequently detected pathogenic POLG mutation in the Caucasian population is c.1399G>A leading to a p.Ala467Thr missense mutation in the linker domain of the protein. Although many patients are homozygous for this mutation, clinical presentation is highly variable, ranging from childhood-onset Alpers-Huttenlocher syndrome to adult-onset sensory ataxic neuropathy dysarthria and ophthalmoparesis. The reasons for this are not clear, but familial clustering of phenotypes suggests that modifying factors may influence the clinical manifestation. In this study, we collected clinical, histological and biochemical data from 68 patients carrying the homozygous p.Ala467Thr mutation from eight diagnostic centres in Europe and the USA. We performed DNA analysis in 44 of these patients to search for a genetic modifier within POLG and flanking regions potentially involved in the regulation of gene expression, and extended our analysis to other genes affecting mitochondrial DNA maintenance (POLG2, PEO1 and ANT1). The clinical presentation included almost the entire phenotypic spectrum of all known POLG mutations. Interestingly, the clinical presentation was similar in siblings, implying a genetic basis for the phenotypic variability amongst homozygotes. However, the p.Ala467Thr allele was present on a shared haplotype in each affected individual, and there was no correlation between the clinical presentation and genetic variants in any of the analysed nuclear genes. Patients with mitochondrial DNA haplogroup U developed epilepsy significantly less frequently than patients with any other mitochondrial DNA haplotype. Epilepsy was reported significantly more frequently in females than in males, and also showed an association with one of the chromosomal markers defining the POLG haplotype. In conclusion, our clinical results show that the homozygous p.Ala467Thr POLG mutation does not cause discrete phenotypes, as previously suggested, but rather there is a continuum of clinical symptoms. Our results suggest that the mitochondrial DNA background plays an important role in modifying the disease phenotype but nuclear modifiers, epigenetic and environmental factors may also influence the severity of disease.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Vivienne C M
authors.initials: VC
authors.lastname: Neeve
authors.forename: David C
authors.initials: DC
authors.lastname: Samuels
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Bindoff
authors.forename: Bianca
authors.initials: B
authors.lastname: van den Bosch
authors.forename: Gert
authors.initials: G
authors.lastname: Van Goethem
authors.forename: Hubert
authors.initials: H
authors.lastname: Smeets
authors.forename: Anne
authors.initials: A
authors.lastname: Lombès
authors.forename: Claude
authors.initials: C
authors.lastname: Jardel
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: Salvatore
authors.initials: S
authors.lastname: Dimauro
authors.forename: Maaike
authors.initials: M
authors.lastname: De Vries
authors.forename: Jan
authors.initials: J
authors.lastname: Smeitink
authors.forename: Bart W
authors.initials: BW
authors.lastname: Smits
authors.forename: Ireneus F M
authors.initials: IF
authors.lastname: de Coo
authors.forename: Carsten
authors.initials: C
authors.lastname: Saft
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Bianca-Cortina
authors.initials: BC
authors.lastname: Keiling
authors.forename: Birgit
authors.initials: B
authors.lastname: Czermin
authors.forename: Angela
authors.initials: A
authors.lastname: Abicht
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Gavin
authors.initials: G
authors.lastname: Hudson
authors.forename: Grainne G
authors.initials: GG
authors.lastname: Gorman
authors.forename: Doug M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000409:Alanine / Q000235:genetics; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000235:genetics* / Q000401:mortality; D005060:Europe; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000401:mortality; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics* / Q000401:mortality; D013223:Statistics as Topic; D018709:Statistics, Nonparametric; D013912:Threonine / Q000235:genetics; D055815:Young Adult
chemical_list: D013912:Threonine; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D000409:Alanine