title: Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland.
abstract: We describe a founder mutation in the gene encoding ganglioside-induced differentiation associated-protein 1 (GDAP1), leading to amino acid change p.H123R, as a common cause of autosomal dominant axonal Charcot-Marie-Tooth (CMT2) neuropathy in Finland. The mutation explains up to 14 % of CMT2 in Finland, where most patients with axonal neuropathy have remained without molecular diagnosis. Only three families out of 28 were found to carry putative disease mutations in the MFN2 gene encoding mitofusin 2. In addition, the MFN2 variant p.V705I was commonly found in our patients, but we provide evidence that this previously described mutation is a common polymorphism and not pathogenic. GDAP1-associated polyneuropathy caused predominantly a mild and slowly progressive phenotype. Besides distal leg muscle weakness, most patients showed mild proximal weakness, often with asymmetry and pes cavus. Our findings broaden the understanding of GDAP1 mutations in CMT2 phenotypes and provide support for the use of whole-exome sequencing in CMT gene diagnostics.
authors: Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Finland.
authors: Mari
authors: M
authors: Auranen
authors: Emil
authors: E
authors: Ylikallio
authors: Jussi
authors: J
authors: Toppila
authors: Mirja
authors: M
authors: Somer
authors: Sari
authors: S
authors: Kiuru-Enari
authors: Henna
authors: H
authors: Tyynismaa
mesh_terms: D000293:Adolescent; D000328:Adult; D001369:Axons / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology; D002648:Child; D005387:Finland; D020558:GTP Phosphohydrolases / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011115:Polyneuropathies / Q000209:etiology / Q000235:genetics; D055815:Young Adult
chemical_list: C118663:GDAP protein; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D020558:GTP Phosphohydrolases