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• W2972804672 abstract "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. Disclosure: Dr. Cline has nothing to disclose. Dr. Andring has nothing to disclose. Dr. McKenna has received personal compensation in an editorial capacity for Acta Crystallographica. Dr. McKenna holds stock and/or stock options in StrideBio, Mavis Agbandje-McKenna, which sponsored research in which Dr. McKenna was involved as an investigator. Dr. McKenna holds stock and/or stock options in StrideBio, Mavis Agbandje-McKenna. Dr. Subramony has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron Pharma. Dr. Subramony has received research support from Acceleron, Reata, Takeda, Horizon, and Biohaven." @default.
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• W2972804672 date "2019-04-09" @default.
• W2972804672 modified "2023-09-23" @default.
• W2972804672 title "Variant of Uncertain Significance in Charcot Marie Tooth Disease: GDAP1 Protein Modeling and Phenotype Correlation (P3.4-039)" @default.
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