Supplementary MaterialsSupTab_1-8. can be shared will be released via a Material Transfer Agreement. All gene, transcript and protein sequences can be found at NCBI and Ensembl databases (accession numbers are provided in Methods section). Abstract Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a novel mechanism for rare and common NMDA diseases resulting from collagen secretion deficits. Using zebrafish genetic screen, we identified the gene to be essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically decided expression of is usually associated with musculoskeletal and dental conditions. Whole exome sequencing (WES) identified individuals homozygous-by-descent for a rare variant in mutations lead to cranio-lenticulo-sutural-dysplasia (CLSD), a disease characterized by craniofacial and skeletal defects16. These studies established zebrafish as a powerful tool to study procollagen transport and model skeletal conditions. Though ER-to-Golgi transport of procollagen is usually relatively well-studied, how procollagen is usually transported from the Golgi to plasma membrane 17,18 and the medical phenome19 resulting from dysfunction of this process remains a long-standing knowledge gap. We show here that Ric1 and its binding partner, Rgp1, are required to activate Rab6a for procollagen transport through the Trans Golgi Network (TGN) and skeletal development in zebrafish models. We investigated human phenotypes associated with the genetically reduced expression of in phenome-linked DNA biobanks. Clinical re-evaluation of subjects previously found to be homozygous-by-descent for a variant and zebrafish knockouts validated common-disease phenome in these subjects, including abnormal tooth development and interest FLNC deficit hyperactivity disorder (ADHD). This breakthrough allowed us to spell it out a NMDA novel hereditary syndrome, termed CATIFA now, and create the mechanistic continuum between specific symptoms of a Mendelian disease and complicated NMDA traits. Outcomes: RIC1 is necessary for regular skeletogenesis Browsing for novel the different parts of the procollagen secretory pathway with important jobs in skeletal biology, we characterized the zebrafish craniofacial (locus to recognize mutations in the gene (KIAA1432, ENSDARG00000063362 in Zv9), (Fig. 1a; Prolonged Data Fig. 1a-?-c).c). By immediate sequencing of cDNAs through the three indie alleles, we determined a missense mutation within a conserved residue (R882C) in (Fig. 1a). Ric1 is certainly an extremely evolutionarily conserved proteins sharing 71% identification from zebrafish to individual. The fungus and individual homologs of Ric1 proteins and its own binding partner Rgp1 had been shown to become a guanine nucleotide exchange aspect (GEF) for Rab6 GTPase21,22. Nevertheless, the role of Ric1-Rgp1-Rab6a in the context of vertebrate physiology and development is not established. Open in another window Body 1. Ric1 is necessary for craniofacial skeleton form and advancement.a, Zebrafish Ric1 proteins is highly conserved with 81% similarity to human RIC1 (Clustal Omega, EMBL-EBI). Positional cloning identified mutations in alleles (mRNA, show rescue of jaw protrusion (arrowheads) and elongation of the body length (arrows). Quantification of the rescue experiments, head in f, and body length in g. Statistical comparison by two-tailed Mann-Whitney U-test, CI = 95%, n=3 impartial animals for 8, color-coded to match the cells in k. Lines indicate mean and standard deviations in f, g and l. The zebrafish mutant embryos, but they are malformed and smaller than WT controls (Fig. 1d, Extended Data Fig. 1d,?,e).e). Human RIC1 (hRIC1) overexpression by mRNA was sufficient, in genetic alternative experiments, to restore jaw protrusion (Fig. 1e), head and body length in genes.