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

Argente, Jesús; Flores, Raquel Z.; Gutiérrez-Arumí, Armand; Verma, Bhupendra; Martos Moreno, Gabriel Ángel; Cuscó, I.; Oghabian, Ali; Chowen, Julie Ann; Frilander, Mikko J.; Pérez-Jurado, Luis A.

UAM_Biblioteca

Author

Argente, Jesús; Flores, Raquel Z.; Gutiérrez-Arumí, Armand; Verma, Bhupendra; Martos Moreno, Gabriel Ángel

; Cuscó, I.; Oghabian, Ali; Chowen, Julie Ann; Frilander, Mikko J.; Pérez-Jurado, Luis A.

Entity

UAM. Departamento de Pediatría

Publisher

John Wiley & Sons, Inc

Date

2014-03-01

Citation

EMBO Molecular Medicine 6.3 (2014): 299-306

ISSN

1757-4676 (print); 1757-4684 (online)

DOI

10.1002/emmm.201303573

Funded by

This work was supported by the Spanish Ministry of Science and Innovation with the help of European FEDER funding (FIS PI10/0747 to JA, FIS PI10/2512 to LAPJ), the Network Centers for Biomedical Research on Obesity and Nutrition (CIBERobn) and on Rare Diseases (CIBERER) Instituto Carlos III, Fundación Endocrinología y Nutrición, and Academy of Finland and Sigrid Juselius Foundation (to MJF). Antibodies for U11/U12‐65K protein and the purified U11/U12 di‐snRNP were obtained from Dr Reinhard Lührmann (MPI Göttingen). Cell line transformation was performed at the Spanish National DNA Biobank and exome sequencing was performed at qGenomics Laboratories, S.L.

Editor's Version

http://dx.doi.org/10.1002/emmm.201303573

Subjects

mRNA splicing; Pituitary hypoplasia; U12-type introns; Medicina

URI

http://hdl.handle.net/10486/662774

Rights

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

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