Molecular Characteristics
RIC1 (RIC1 Homolog, RAB6A GEF Complex Partner 1) is located on chromosome 9 at the 9p24.1 locus. This gene encodes a protein that functions as a guanine nucleotide exchange factor (GEF) for the Rab6 GTPase. RIC1 plays a crucial role in intracellular transport, particularly in the trafficking of procollagen. The protein is part of the Ric1-Rgp1 complex, which is involved in regulating the secretion of procollagen by activating Rab6a, facilitating its transport from the Golgi apparatus to the extracellular matrix.
Mutations and Pathophysiology
Mutations in the RIC1 gene have been implicated in CATIFA syndrome, a rare genetic disorder characterized by a combination of congenital anomalies. Patel et al. (2017) first described the syndrome in two unrelated male patients from consanguineous families, both homozygous for the same R1265P missense mutation. These patients exhibited syndromic cataracts, global developmental delay, microcephaly, and brain atrophy, with or without cleft lip and palate. Further investigation by Unlu et al. (2020) identified eight affected children. The specific pathogenic variant, c.3794C>G (p.R1265P), seems to affect normal splicing, leading to a transcript that either contains a missense mutation (R1265P) or undergoes intron retention resulting in a premature stop codon and likely nonsense-mediated decay.
Functional studies in zebrafish models have demonstrated that Ric1 is essential for procollagen trafficking. Ric1-deficient zebrafish exhibit significant intracellular retention of procollagen in chondrocytes and fibroblasts, resulting in skeletal and craniofacial abnormalities. These findings suggest that RIC1 mutations disrupt the normal secretion of procollagen, leading to the phenotypic manifestations observed in CATIFA syndrome patients as reported by Unlu et al. (2020).
RIC1