Abstract Details

Title Variant of Uncertain Significance in Charcot Marie Tooth Disease: GDAP1 Protein Modeling and Phenotype Correlation

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 12-039

Objective With increasing availability of gene sequencing for neuromuscular diseases, variants of unknown significance (VUS) are increasingly reported while their pathogenic importance remains uncertain. Documenting such variants together with the appropriate phenotype and possible role in disease is important. We report a woman with a phenotype consistent with Charcot Marie Tooth (CMT) disease and a VUS in the GDAP1 gene together with in silico data to suggest this variant is indeed pathogenic.

Background Although incompletely characterized, GDAP1 plays a role in mitochondrial structure and function. Many known CMT associated mutations cause GDAP1 trafficking issues where GDAP1 doesn't localize to the mitochondria.

Design/Methods The patient is a 36 year old woman with upper extremity weakness starting at age 3. Her parents, siblings and daughter had no similar disorder. Using the structure of glutathione-dependent β-etherase LigF (Helmich et al. 2016) which retains over 20% sequence identity with GDAP1, an in silico model of GDAP1 was generated utilizing the program Swiss-Model.

Results Examination showed normal mental state and cranial nerves with severe lower limb weakness (distal 1/5, proximal 1-3/5), severe distal arm weakness (2/5), but intact proximal arm strength. She was areflexic with polymodal distal sensory loss in the legs. Outside nerve conduction data was compatible with axonal neuropathy. Targeted CMT gene testing revealed a homozygous VUS in GDAP1 (Pro231Leu) and a heterozygous VUS in ATL (Ser314Pro). Her severe axonal polyneuropathy is more consistent with a GDAP1 mutation which causes autosomal recessive CMT. Modeling showed P231 is located on the surface and end of a long alpha helix, likely contributing to a recognition motif. Prolines at the end of alpha helices are known “helix breakers” and therefore we hypothesize this residue plays a crucial role in the protein’s fold.

Conclusions

Residue P231 is important for recognition and mitochondrial trafficking, suggesting this Pro231Leu VUS is pathogenic in CMT disease.

Authors/Disclosures
Laura Cline PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
S H. Subramony, MBBS, FAAN (University of Florida)	Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avidity. Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Dyne. Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lupin. Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Fallonmedica. Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amicus. Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Fulcrum. The institution of Dr. Subramony has received research support from Reata. The institution of Dr. Subramony has received research support from Retrotope. The institution of Dr. Subramony has received research support from Acceleron. The institution of Dr. Subramony has received research support from Biohaven. The institution of Dr. Subramony has received research support from Pharnext. The institution of Dr. Subramony has received research support from Fulcrum. The institution of Dr. Subramony has received research support from National Ataxia Foundation. The institution of Dr. Subramony has received research support from Friedreich Ataxia Research Alliance. The institution of Dr. Subramony has received research support from Muscular Dystrophy Association. The institution of Dr. Subramony has received research support from Univ of Rochester, MDA. The institution of Dr. Subramony has received research support from Virginia Commonwealth Univ (FDA, Wyck Foundation)). The institution of Dr. Subramony has received research support from Children's Hospital, Philadelphia (FDA). The institution of Dr. Subramony has received research support from Houston Methodist (NIH). The institution of Dr. Subramony has received research support from NIHR01 AR076060-01A1 . The institution of Dr. Subramony has received research support from NIH2R42HD089804-04 . The institution of Dr. Subramony has received research support from NIH R01 AR056973 . The institution of Dr. Subramony has received research support from FSHD Society. The institution of Dr. Subramony has received research support from AAVANTI BIO. The institution of Dr. Subramony has received research support from COHAV FL State Dept of Health. The institution of Dr. Subramony has received research support from Avidity. The institution of Dr. Subramony has received research support from PTC. The institution of Dr. Subramony has received research support from Biohaven. The institution of Dr. Subramony has received research support from Fulcrum. The institution of Dr. Subramony has received research support from Vertex. The institution of Dr. Subramony has received research support from Arthrex.

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