Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.
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.
Horvath
Rita
R
Metabolic Diseases Centre, Munich-Schwabing, Institutes of Clinical Chemistry, Molecular Diagnostics and Mitochondrial Genetics, Academic Hospital Schwabing Munich, Germany.
Hudson
Gavin
G
Ferrari
Gianfrancesco
G
Fütterer
Nancy
N
Ahola
Sofia
S
Lamantea
Eleonora
E
Prokisch
Holger
H
Lochmüller
Hanns
H
McFarland
Robert
R
Ramesh
V
V
Klopstock
Thomas
T
Freisinger
Peter
P
Salvi
Fabrizio
F
Mayr
Johannes A
JA
Santer
Rene
R
Tesarova
Marketa
M
Zeman
Jiri
J
Udd
Bjarne
B
Taylor
Robert W
RW
Turnbull
Douglass
D
Hanna
Michael
M
Fialho
Doreen
D
Suomalainen
Anu
A
Zeviani
Massimo
M
Chinnery
Patrick F
PF
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
D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human