Abstract
The 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.Subject Categories Genetics, Gene Therapy ' Genetic Disease; Metabolism
Highlights
Familial dwarfism with isolated growth hormone (GH) deficiency (IGHD) can be caused by mutations in GH1 and other genes involved in GH regulation and pituitary development (Pf€affle et al, 2011)
We identified biallelic mutations in the RNPC3 gene coding for the minor spliceosome U11/U12-65K protein as a novel mechanism associated with IGHD and pituitary hypoplasia in three cases from a single family
U11/U12-65K protein levels are strictly regulated (Verbeeren et al, 2010), as it is an essential component of the intron-recognition complex (U11/U12 disnRNP) in the ubiquitous minor spliceosome (Benecke et al, 2005) involved in splicing of approximately 700 target genes
Summary
Familial dwarfism with isolated growth hormone (GH) deficiency (IGHD) can be caused by mutations in GH1 and other genes involved in GH regulation and pituitary development (Pf€affle et al, 2011). Splicing is performed by spliceosomes, ribonucleoprotein complexes containing numerous proteins and five small nuclear RNAs (snRNAs). The major U2-dependent spliceosome processes most introns, while a small subset (
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