Phenotypic spectrum associated with mutations of the mitochondrial polymerase γ gene

被引:295
作者
Horvath, Rita
Hudson, Gavin
Ferrari, Gianfrancesco
Fuetterer, Nancy
Ahola, Sofia
Lamantea, Eleonora
Prokisch, Holger
Lochmueller, Hanns
McFarland, Robert
Ramesh, V.
Klopstock, Thomas
Freisinger, Peter
Salvi, Fabrizio
Mayr, Johannes A.
Santer, Rene
Tesarova, Marketa
Zeman, Jiri
Udd, Bjarne
Taylor, Robert W.
Turnbull, Douglass
Hanna, Michael
Fialho, Doreen
Suomalainen, Anu
Zeviani, Massimo
Chinnery, Patrick F.
机构
[1] Acad Hosp Schwabing, Inst Clin CHem Mol Diagnost & Mitochondrial Genet, Metab Dis Ctr, Munich, Germany
[2] Childrens Hosp, Matab Dis Ctr, Munich, Germany
[3] Tech Univ Munich, Inst Med Genet, D-8000 Munich, Germany
[4] Univ Munich, Friedrich Baur Inst, Munich, Germany
[5] Univ Munich, Dept Neurol, Munich, Germany
[6] GSF, Res Ctr Environm & Hlth, Inst Human Genet, Neuherberg, Germany
[7] Univ Hamburg, Med Ctr Eppendorf, Dept Pediat, Hamburg, Germany
[8] Newcastle Univ, Mitochondrial Res Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England
[9] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England
[10] Newcastle Gen Hosp, Dept Paediat Neurol, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England
[11] UCL, Inst Neurol, Dept Mol Neurosci, London, England
[12] Natl Neurol Inst, Pierfranco & Luisa Mariani Ctr Study Childrens Mi, Unit Mol Neurogenet, Milan, Italy
[13] Osped Bellaria, Dept Neurosci, Neurol Unit, Bologna, Italy
[14] Univ Helsinki, Dept Med Genet, Programme Neurosci, FIN-00014 Helsinki, Finland
[15] Vaasa Cent Hosp, Dept Neurol, Vaasa, Finland
[16] Paracelsus Med Univ, Pediat Clin, Salzburg, Austria
[17] Charles Univ Prague, Fac Med, Dept Pediat, Prague, Czech Republic
[18] Charles Univ Prague, Fac Med, Ctr Appl Genom, Prague, Czech Republic
基金
英国医学研究理事会; 英国惠康基金;
关键词
mitochondrial encephalopathy; mitochondrial DNA; polymerase gamma; mtDNA; chronic progressive external ophthalmoplegia; Alpers syndrome;
D O I
10.1093/brain/awl088
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
引用
收藏
页码:1674 / 1684
页数:11
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