Missense Mutation in SCGN (Secretagogin) as a Possible Cause of Ulcerative Colitis in Three Siblings
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Inflammatory bowel disease (IBD) consists of two disorders, Crohn's disease and ulcerative colitis (UC), which affect 1.4 million Americans. Genetic factors contribute to the development of these disorders but not all culprit genes have been identified. To further our understanding of the genetic causes of IBD, we examined a consanguinous family with a high incidence of childhood-onset UC. We performed exome sequencing of five siblings, three of which were diagnosed with severe UC before the age of 10. Given the parents' consanguinity, areas of homozygosity were examined using a SNP array. Two areas of homozygosity, in chromosomes 6 and 12, were shared by the three affected probands but not by their two unaffected siblings. Given the inheritance pattern in the pedigree, we speculated that a homozygous recessive mutation in a gene contained within these intervals should be responsible for the phenotype. Thus, a total of 140 potential genes were implicated. Variants found by exome sequencing were prioritized if they affected the three probands and not their unaffected siblings, and if they were rare in the general population according to their frequency in the 1000 genomes database. Afterwards, we cross-referenced the identified potential culprit variants found in the exome sequence analysis against the unique areas of homozygosity shared by the probands. The top candidate change was in SCGN, which had a coding variant (c. 433G>A/p.R77H) not previously found in the 1000 genomes database or in the dbSNP database. Sanger sequencing confirmed that both parents were carriers, the three probands were homozygous, and one sibling was a carrier while the other was wild-type. SCGN encodes a 276 amino acid, calcium-binding protein, secretagogin. The protein is expressed in tissues of neuroendocrine lineage, such as pancreatic β-cells and intestinal enteroendocrine cells. The coding change found in these patients is located in one of the calcium binding domains (EF hand 2). Immunohistochemical analyses of the patients' colon biopsies did not demonstrate a decrease of the presence of secretagogin when compared to controls, suggesting that the mutation does not affect expression, but may have a functional effect yet to be determined. We are building a molecular and cellular model of the R77H mutation to identify if this coding change alters the function of the protein. If a functional impairment of SCGN is confirmed, it could represent the first description of enteroendocrine dysfunction playing a role in IBD pathophysiology.