Proteomic interactome analyses of Glypican 1 and a putative disease modifying variant

In an 8-year-old girl of consanguineous Turkish parents, who developed ataxic gait and polyneuropathy at the age of 3 years, we identified a biallelic missense variant c.424C>T, p.R142W in Glypican 1 (GPC1) by using whole genome sequencing. Up to date, GPC1 has not been associated with a neuromuscular disorder and we hypothesized that this variant, which is predicted as deleterious (CADD score 26.4) may be causative for the disease. Using mass spectrometry-based proteomics, we investigated the interactome of the GPC1 missense variant. We identified 198 proteins interacting with GPC1, of which 16 were altered due to the missense variant. Differentially regulated proteins include members of the vacuolar ATPase (v-ATPase) and mammalian target of rapamycin complex 1 (mTORC1) complexes, whose mis-regulation could have a potential impact on disease severity in the patient. Importantly, these proteins are novel interaction partners of GPC1. At 11 years of age, the patient developed a cardiomyopathy and kyphoscoliosis and a Friedreich’s Ataxia (FRDA) was suspected. Indeed a 104 GAA-repeat expansion in the FXN gene was found. Given the unusually severe phenotype in a patient with FRDA carrying only 104 GAA-repeats, we currently assume that the disturbed function in GPC1 may exacerbate the disease phenotype.