Defective minor spliceosome mRNA processing results in isolated familial growth hormone deficiency.
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.
Departments of Endocrinology and Pediatrics, Hospital Infantil Universitario Niño Jesús Universidad Autónoma de Madrid, Madrid, Spain.
Jesús
J
Argente
Raquel
R
Flores
Armand
A
Gutiérrez-Arumí
Bhupendra
B
Verma
Gabriel Á
GÁ
Martos-Moreno
Ivon
I
Cuscó
Ali
A
Oghabian
Julie A
JA
Chowen
Mikko J
MJ
Frilander
Luis A
LA
Pérez-Jurado
D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000595:Amino Acid Sequence; D001921:Brain / Q000000981:diagnostic imaging; D002648:Child; D018389:Codon, Nonsense; D004393:Dwarfism, Pituitary / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007438:Introns; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D011859:Radiography; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA
C573916:ARPC5 protein, human; D051376:Actin-Related Protein 2-3 Complex; D018389:Codon, Nonsense; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C498172:RNPC3 protein, human; D017411:Ribonucleoproteins, Small Nuclear; C098762:U11 small nuclear ribonucleoprotein, human; C552126:U11-U12 small nuclear ribonucleoprotein