Defective minor spliceosome mRNA processing results in isolated familial growth hormone deficiency

摘要

AbstractThe molecular basis of a significant number of cases of isolated growth hormone deficiency remains unknown. We describe three sisters affected with severe isolated growth hormone deficiency and pituitary hypoplasia caused by biallelic mutations in the RNPC3 gene, which codes for a minor spliceosome protein required for U11/U12 small nuclear ribonucleoprotein (snRNP) formation and splicing of U12-type introns. We found anomalies in U11/U12 di-snRNP formation and in splicing of multiple U12-type introns in patient cells. Defective transcripts include preprohormone convertases SPCS2 and SPCS3 and actin-related ARPC5L genes, which are candidates for the somatotroph-restricted dysfunction. The reported novel mechanism for familial growth hormone deficiency demonstrates that general mRNA processing defects of the minor spliceosome can lead to very narrow tissue-specific consequences.SynopsisThis is the first report of the implication of a minor spliceosome mutation in human disease. Specifically, isolated growth hormone deficiency due to a pituitary development defect affecting somatotrophs can derive from aberrant RNA splicing by RNPC3.Isolated growth hormone deficiency can be caused by aberrant RNA splicing by the minor spliceosome.Pituitary hypoplasia associated with a phenotype of growth hormone deficiency suggests that mutation of the RNPC3 gene results in a defect in pituitary development specifically affecting somatotrophs.Mutation of the RNPC3 gene resulted in relative levels of unspliced or aberrantly spliced U12-type introns from 5 to 30% of the spliced mRNA level.