ClinVar

In a large 5-generation Austrian family (family 1) with the periodontal type of Ehlers-Danlos syndrome (EDSPD1; 130080), Kapferer-Seebacher et al. (2016) identified heterozygosity for a c.149_150TC-AT change (c.149_150TC-AT, NM_001733.4) in the C1R gene, resulting in a val50-to-asp substitution (val32-to-asp (V32D) in the mature protein) at an evolutionarily conserved residue within the CUB1 collagen-binding domain. The mutation segregated fully with disease in the family, and was not found in the ExAC, 1000 Genomes Project, ClinVar, or dbSNP (March 2016) databases. Western blots of HEK293 cells and supernatants in which V50D had been overexpressed indicated that the abnormal C1R protein was retained in the cell but could undergo autoactivation that might lead to interaction with off-target substrates. In addition, mutation-transfected cells showed an increased proportion of dilated cisternae of the rough endoplasmic reticulum compared to controls. Kapferer-Seebacher et al. (2016) noted that unlike previously reported families with EDSPD, none of the affected individuals in this family exhibited pretibial discoloration.