Toggle Main Menu Toggle Search

Open Access padlockePrints

What is influencing the phenotype of the common homozygous polymerase-gamma mutation p.Ala467Thr?

Lookup NU author(s): Vivienne Neeve, Professor Hanns Lochmuller, Professor Gavin Hudson, Professor Grainne Gorman, Emeritus Professor Doug Turnbull, Professor Robert Taylor, Professor Patrick Chinnery, Professor Rita HorvathORCiD

Downloads


Abstract

Polymerase-gamma (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.


Publication metadata

Author(s): Neeve VCM, Samuels DC, Bindoff LA, van den Bosch B, Van Goethem G, Smeets H, Lombes A, Jardel C, Hirano M, DiMauro S, De Vries M, Smeitink J, Smits BW, de Coo IFM, Saft C, Klopstock T, Keiling BC, Czermin B, Abicht A, Lochmuller H, Hudson G, Gorman GG, Turnbull DM, Taylor RW, Holinski-Feder E, Chinnery PF, Horvath R

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2012

Volume: 135

Issue: 12

Pages: 3614-3626

Print publication date: 01/12/2012

Date deposited: 13/02/2013

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/brain/aws298

DOI: 10.1093/brain/aws298


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
UK NIHR Biomedical Research Centre for Ageing and Age-related disease award
UK Parkinson's Disease Society
Medical Research Council (UK)
UK NHS
01GM0862German Ministry of Education and Research (BMBF, Bonn, Germany)
906919Wellcome Trust Centre for Mitochondrial Research
G1000848Medical Research Council (UK)
GM073744NIH

Share