Co-occurrence of four nucleotide changes associated with an adult mitochondrial ataxia phenotype

Mitochondrial DNA maintenance disorders are an important cause of hereditary ataxia syndrome, and the majority are associated with mutations in the gene encoding the catalytic subunit of the mitochondrial DNA polymerase (DNA polymerase gamma), POLG. Mutations resulting in the amino acid substitution...

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Bibliographic Details
Published in:BMC research notes 2014-12, Vol.7 (1), p.883-883, Article 883
Main Authors: Zabalza, Ramón, Nurminen, Anssi, Kaguni, Laurie S, Garesse, Rafael, Gallardo, M Esther, Bornstein, Belén
Format: Article
Language:English
Subjects:
Aged
Alleles
Amino Acid Sequence
Amino Acid Substitution
Amino acids
Analysis
Ataxia
Base Sequence
Care and treatment
Cerebellar Ataxia - genetics
Cerebellar Ataxia - physiopathology
Diagnosis
DNA Polymerase gamma
DNA polymerases
DNA, Mitochondrial - genetics
DNA-Directed DNA Polymerase - genetics
Female
Genes
Genetic aspects
Genotype
Humans
Male
Middle Aged
Mitochondria - genetics
Mitochondria - pathology
Mitochondrial DNA
Models, Molecular
Molecular Sequence Data
Mutation
Pedigree
Phenotype
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Summary:Mitochondrial DNA maintenance disorders are an important cause of hereditary ataxia syndrome, and the majority are associated with mutations in the gene encoding the catalytic subunit of the mitochondrial DNA polymerase (DNA polymerase gamma), POLG. Mutations resulting in the amino acid substitutions A467T and W748S are the most common genetic causes of inherited cerebellar ataxia in Europe. We report here a POLG mutational screening in a family with a mitochondrial ataxia phenotype. To evaluate the likely pathogenicity of each of the identified changes, a 3D structural analysis of the PolG protein was carried out, using the Alpers mutation clustering tool reported previously. Three novel nucleotide changes and the p.Q1236H polymorphism have been identified in the affected members of the pedigree. Computational analysis suggests that the p.K601E mutation is likely the major contributing factor to the pathogenic phenotype. Computational analysis of the PolG protein suggests that the p.K601E mutation is likely the most significant contributing factor to a pathogenic phenotype. However, the co-occurrence of multiple POLG alleles may be necessary in the development an adult-onset mitochondrial ataxia phenotype.
ISSN:1756-0500
1756-0500
DOI:10.1186/1756-0500-7-883