Novel Mutation in VCP Causes Charcot-Marie-Tooth Type 2 (CMT2) Phenotype (I5-1.004)

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OBJECTIVE: A novel missense mutation in VCP caused adult-onset axonal CMT in a large family. BACKGROUND: CMT2 is an inherited, axonal, peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and normal or near-normal nerve conduction velocities. The genetic cause of symptoms cannot be identified for most families with CMT2. Exome sequencing can help identify the genetic causes of unknown forms of CMT. DESIGN/METHODS: A family of eight was evaluated by neurological examination and electrophysiology, determining that five were affected with a length-dependent sensorimotor neuropathy with intermediate nerve conduction velocities. Testing for known genes associated with CMT2 was negative. Exome sequencing identified a novel E185K missense mutation in VCP. Mutations in VCP have previously been shown to cause Inclusion Body Myopathy with early-onset Paget disease and Frontotemporal Dementia (IBMPFD). Sanger sequencing was performed on family members to determine disease segregation. Functional assays were performed to determine pathogenicity. RESULTS: The mutation cosegregated with disease in the family. The mutation is located within the L1 domain of the VCP protein. Assays comparing the E185K mutation to WT and known pathogenic A232E mutation showed that E185K caused an increase in markers p62 and LC3-II. Human p97 ATPase activity was compared between WT, E185K, and pathogenic mutations (R93C, L198W, R155H, and A232E). E185K caused an increase in ATPase activity, though not to the equivalent of other mutations. CONCLUSIONS: The E185K mutation is causing CMT2 in this family. The mutation cosegregated with disease and caused increases in markers p62 and LC3-II, along with human p97 ATPase, evidence of pathogenicity. This is the most recent example of a protein in the ubiquitous 3 ligase pathway causing CMT. The ATPase activity caused by E185K was not elevated as significantly as levels caused by other mutations. This could suggest a phenotype/genotype correlation related to symptom severity. Study Supported by: Inherited Neuropathy Consortium part of the NIH Rare Diseases Clinical Research Network (grant#1U54NS065712-01) Disclosure: Dr. Feely has nothing to disclose. Dr. Gonzalez has nothing to disclose. Dr. Weihl has received personal compensation for activities with Link Medicine and Pfizer Inc. Dr. Weihl has received research support from Link Medicine. Dr. Shy has nothing to disclose. Dr. Zuchner has received license fee payments from Athena Diagnostics.

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