Poster Presentation 9th GeneMappers Conference 2012

The Pathogenecity of V705I Variant in CMT2: A Lesson from Scanning MFN2 Gene in an Australian Family. (#104)

Obaid Albulym 1 2 , Danqing Zhu 3 , Stephen Reddel 1 2 3 , Marina Kennerson 1 2 3 , Garth Nicholson 1 2 3
  1. ANZAC Research Institute, Concord, NSW, Australia
  2. Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  3. Molecular Medicine Laboratory, Concord Hospital, Concord, NSW, Australia

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of disorders affecting both motor and sensory neurons in the peripheral nervous system. CMT has traditionally been classified into two major types; demyelinating (CMT1) and the axonal (CMT2) form of the disease. Mutations in the mitochondrial mitofusin-2 (MFN2) gene (MIM#608507) are considered to be the most common cause for CMT21 . MFN2 is involved in mitochondrial fusion and the maintenance of mitochondrial morphology2 . Numerous studies have reported MFN2 mutations in which the majority are point mutations3 . We have identified the V705I variant of MFN2 in a patient from a multi-generation Australian family (CMT105) diagnosed with CMT2. The V705I variant in MFN2 has been previously reported as disease causing mutation in families with CMT245  . To determine if this variant is the cause of CMT2 in the family, we performed segregation analysis and tested the variant in a cohort of ethnically matched controls of English descent. We showed that the V705I variant did not segregate with the disease phenotype in the family and was present in control individuals with an allele frequency of 4.4%. We have shown that the V705I variant is a polymorphism and not disease causing in our family. As this is a previously reported mutation, our study highlights the importance of variant validation by phenotype segregation and genotyping in ethnically matched controls. 

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  2. Eura, Y., et al., Two mitofusin proteins, mammalian homologues of FZO, with distinct functions are both required for mitochondrial fusion. J Biochem, 2003. 134(3): p. 333-44.
  3. http://www.molgen.ua.ac.be/CMTMutations/Mutations/Mutations.cfm. 2012 [cited 2012.
  4. Engelfried, K., et al., Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2). BMC Med Genet, 2006. 7: p. 53.
  5. Braathen, G.J., et al., MFN2 point mutations occur in 3.4% of Charcot-Marie-Tooth families. An investigation of 232 Norwegian CMT families. BMC Med Genet, 2010. 11: p. 48.