A Balanced Translocation in Kallmann Syndrome Implicates a Long Noncoding RNA, RMST, as a GnRH Neuronal Regulator.
Adult
Chromosomes, Human, Pair 12
/ genetics
Chromosomes, Human, Pair 7
/ genetics
Genome-Wide Association Study
Gonadotropin-Releasing Hormone
/ genetics
Humans
Induced Pluripotent Stem Cells
/ metabolism
Kallmann Syndrome
/ genetics
Male
Neural Crest
/ metabolism
Prognosis
RNA, Long Noncoding
/ genetics
Translocation, Genetic
human
long non-coding RNA
mutations
reproduction
Journal
The Journal of clinical endocrinology and metabolism
ISSN: 1945-7197
Titre abrégé: J Clin Endocrinol Metab
Pays: United States
ID NLM: 0375362
Informations de publication
Date de publication:
01 03 2020
01 03 2020
Historique:
received:
30
08
2019
accepted:
20
09
2019
pubmed:
20
10
2019
medline:
11
11
2020
entrez:
20
10
2019
Statut:
ppublish
Résumé
Kallmann syndrome (KS) is a rare, genetically heterogeneous Mendelian disorder. Structural defects in KS patients have helped define the genetic architecture of gonadotropin-releasing hormone (GnRH) neuronal development in this condition. Examine the functional role a novel structural defect affecting a long noncoding RNA (lncRNA), RMST, found in a KS patient. Whole genome sequencing, induced pluripotent stem cells and derived neural crest cells (NCC) from the KS patient were contrasted with controls. The Harvard Reproductive Sciences Center, Massachusetts General Hospital Center for Genomic Medicine, and Singapore Genome Institute. A KS patient with a unique translocation, t(7;12)(q22;q24). A novel translocation was detected affecting the lncRNA, RMST, on chromosome 12 in the absence of any other KS mutations. Compared with controls, the patient's induced pluripotent stem cells and NCC provided functional information regarding RMST. Whereas RMST expression increased during NCC differentiation in controls, it was substantially reduced in the KS patient's NCC coincident with abrogated NCC morphological development and abnormal expression of several "downstream" genes essential for GnRH ontogeny (SOX2, PAX3, CHD7, TUBB3, and MKRN3). Additionally, an intronic single nucleotide polymorphism in RMST was significantly implicated in a genome-wide association study associated with age of menarche. A novel deletion in RMST implicates the loss of function of a lncRNA as a unique cause of KS and suggests it plays a critical role in the ontogeny of GnRH neurons and puberty.
Identifiants
pubmed: 31628846
pii: 5601163
doi: 10.1210/clinem/dgz011
pmc: PMC7112981
pii:
doi:
Substances chimiques
RNA, Long Noncoding
0
Gonadotropin-Releasing Hormone
33515-09-2
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NICHD NIH HHS
ID : P50 HD028138
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD096324
Pays : United States
Organisme : NIDCR NIH HHS
ID : K99 DE026824
Pays : United States
Organisme : NICHD NIH HHS
ID : K23 HD077043
Pays : United States
Organisme : NIGMS NIH HHS
ID : P01 GM061354
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD081256
Pays : United States
Informations de copyright
© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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