A Balanced Translocation in Kallmann Syndrome Implicates a Long Noncoding RNA, RMST, As a GnRH Neuronal Regulator

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2019 Oct 20

PMID 31628846

Citations 20

Authors

Maria Stamou

Shi-Yan Ng

Harrison Brand

Harold Wang

Lacey Plummer

Lyle Best

Steven Havlicek

Martin Hibberd

Chiea Chuen Khor

James Gusella

Ravikumar Balasubramanian

Michael Talkowski

Lawrence W Stanton

William F Crowley

Affiliations

Soon will be listed here.

Abstract

Context: 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.

Objective: Examine the functional role a novel structural defect affecting a long noncoding RNA (lncRNA), RMST, found in a KS patient.

Design: Whole genome sequencing, induced pluripotent stem cells and derived neural crest cells (NCC) from the KS patient were contrasted with controls.

Setting: The Harvard Reproductive Sciences Center, Massachusetts General Hospital Center for Genomic Medicine, and Singapore Genome Institute.

Patient: A KS patient with a unique translocation, t(7;12)(q22;q24).

Interventions/main Outcome Measure/results: 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.

Conclusions: 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.

Citing Articles

Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.

Andersen R, Alkuraya I, Ajeesh A, Sakamoto T, Mena E, Amr S Hum Genet. 2024; 143(7):921-938.

PMID: 39060644 PMC: 11294402. DOI: 10.1007/s00439-024-02693-y.

Deletion in RMST lncRNA impairs hypothalamic neuronal development in a human stem cell-based model of Kallmann Syndrome.

Ali G, Shin K, Ahmed N, Habbab W, Alkhadairi G, Razzaq A Cell Death Discov. 2024; 10(1):330.

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Rare germline disorders implicate long non-coding RNAs disrupted by chromosomal structural rearrangements.

Andersen R, Alkuraya I, Ajeesh A, Sakamoto T, Mena E, Amr S medRxiv. 2024; .

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Illuminating the terminal nerve: Uncovering the link between GnRH-1 neuron and olfactory development.

Amato Jr E, Taroc E, Forni P J Comp Neurol. 2024; 532(3):e25599.

PMID: 38488687 PMC: 10958589. DOI: 10.1002/cne.25599.

A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome.

Ben-Mahmoud A, Kishikawa S, Gupta V, Leach N, Shen Y, Moldovan O Sci Rep. 2023; 13(1):12984.

PMID: 37563198 PMC: 10415337. DOI: 10.1038/s41598-023-40037-4.

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