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.
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Acknowledgments
The authors would like to thank the patients and their families for participation in the study. Riitta Lehtinen and Annika Stormbom are thanked for technical help. We also acknowledge the exome capture, sequencing and variant calling pipeline analysis performed by the Institute for Molecular Medicine Finland FIMM. The authors wish to thank the following funding sources for support: Sigrid Jusélius Foundation, the Finnish Neuromuscular Disorders Association, and the Academy of Finland.
Web Resources
Inherited Peripheral Neuropathies Mutation Database (www.molgen.ua.ac.be/CMTmutations/Mutations/)
1000Genomes (www.1000Genomes.org)
NHLBI GO Exome Sequencing Project (evs.gs.washington.edu/EVS/)
SIFT Genome (sift.jcvi.org/)
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Mari Auranen and Emil Ylikallio contributed equally.
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ESM 1
Filtering steps of the exome data using the unbiased approach. From each of the families 1 and 2, two related CMT2 patients were subjected to exome sequencing. The number of variants for each filtering step are shown. The selected variants were the following: (1) Intragenic, (2) Heterozygous on autosomes, (3) Rare in the 1000Genomes project (<0.5 % frequency), (4) Nonsynonomous, (5) Predicted damaging by the SIFT Tool, (6) Shared by the two affected family members, (7) Not present in our in-house database of exome data from Finnish individuals (n = 50). (JPEG 61 kb)
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Auranen, M., Ylikallio, E., Toppila, J. et al. Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland. Neurogenetics 14, 123–132 (2013). https://doi.org/10.1007/s10048-013-0358-9
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DOI: https://doi.org/10.1007/s10048-013-0358-9