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.

Unsolved issues related to human mitochondrial diseases

“…The presence of modifying factors could however be demonstrated in diseases due to mutations of the POLG or TK2 nuclear genes and of the mtDNA-encoded ND1, ND4 and ND6 genes causing Leber Hereditary Optic Neuropathy (LHON). They were proposed to underlie the absence of symptoms despite the presence of the mutations in LHON [4] or to significantly modify the presentation in the case of POLG or TK2 [5,6].…”

“…The main candidate genetic modifiers have been the mtDNA haplogroup and nuclear genes encoding mtDNA replication factors [6,7]. Despite longstanding and intensive efforts in the case of LHON the modifying nuclear genes have however remained elusive [8][9][10].…”

Epilepsy: when family history holds the key to diagnosis

“…Presentations range from childhood onset Alpers-Huttenlocher syndrome to adult-onset sensory ataxic neuropathy dysarthria and ophthalmoplegia (SANDO). [4][5][6][7][8][9] Epilepsy is a common presentation of POLG mutations. 6,7 In the majority of patients there is an occipital EEG focus, causing occipital seizures, which are characterised by flickering coloured lights, often persistent for long periods of time; in addition there may also be nystagmus, metamorphopsias and ictal visual loss.…”

Hidden genetic variation : From recognition to acknowledgement of genetic individuality

“…Although many patients are homozygous for this mutation, clinical phenotypes are highly variable. All patients are epileptic, 80% have other neuropathologies and 60% have eye muscle disease [8].…”

“…Monogenic traits have also been studied extensively in humans, in particular monogenic rare diseases like cystic fibrosis (disease of the lung) [4], the Miller syndrome (genetic disorder of facial expression, arms and legs) [5] and specific cases of mitochondrial diseases caused by mutation in polymerase-γ [6]. Mutation in polymerase-γ leads to clumps of diseased mitochondria (the machines where energy is produced) in muscle tissue.…”