In a currently 13-year-old girl of consanguineous Turkish parents, who developed unsteady gait and polyneuropathy at the ages of 3 and 6 years, respectively, whole genome sequencing was performed and a biallelic missense variant c.424C>T, p.R142W in glypican 1 (GPC1) was identified as a putative disease-associated variant. Up to date, GPC1 has not been associated with a neuromuscular disorder, and the authors hypothesized that this variant, predicted as deleterious, may be causative for the disease. Using mass spectrometry-based proteomics, the interactome of GPC1 WT and the missense variant was investigated. 198 proteins interacting with GPC1 were identified, of which 16 were altered for the missense variant. This included CANX as well as vacuolar ATPase (V-ATPase) and the mammalian target of rapamycin complex 1 (mTORC1) complex members, whose dysregulation could have a potential impact on disease severity in the patient. Importantly, these proteins are novel interaction partners of GPC1. At 10.5 years, the patient developed dilated cardiomyopathy and kyphoscoliosis, and Friedreich's ataxia (FRDA) was suspected. Given the unusually severe phenotype in a patient with FRDA carrying only 104 biallelic GAA repeat expansions in FXN, the authors currently speculate that disturbed GPC1 function may have exacerbated the disease phenotype.

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