GOSgene
A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia
GOSgene; Whittaker, DE; Oleari, R; Gregory, LC; Le Quesne-Stabej, P; Williams, HJ; Torpiano, JG; Formosa, N; Cachia, MJ; Field, D; Lettieri, A; Ocaka, LA; Paganoni, AJJ; Rajabali, SH; Riegman, KLH; De Martini, LB; Chaya, T; Robinson, ICAF; Furukawa, T; Cariboni, A; Basson, MA; Dattani, MT
Authors
DE Whittaker
R Oleari
LC Gregory
P Le Quesne-Stabej
HJ Williams
JG Torpiano
N Formosa
MJ Cachia
D Field
A Lettieri
LA Ocaka
AJJ Paganoni
SH Rajabali
KLH Riegman
LB De Martini
T Chaya
ICAF Robinson
T Furukawa
A Cariboni
MA Basson
MT Dattani
Abstract
The positive regulatory (PR) domain containing 13 (PRDM13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis, and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2(+Y) progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia and normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the cooccurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.
Citation
GOSgene, Whittaker, D., Oleari, R., Gregory, L., Le Quesne-Stabej, P., Williams, H., …Dattani, M. (2021). A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia. Journal of Clinical Investigation, 131(24), https://doi.org/10.1172/JCI141587
Journal Article Type | Article |
---|---|
Acceptance Date | Oct 27, 2021 |
Publication Date | Dec 15, 2021 |
Deposit Date | Jul 26, 2023 |
Publicly Available Date | Jul 26, 2023 |
Print ISSN | 0021-9738 |
Publisher | American Society for Clinical Investigation |
Peer Reviewed | Peer Reviewed |
Volume | 131 |
Issue | 24 |
DOI | https://doi.org/10.1172/JCI141587 |
Keywords | GONADOTROPIN-RELEASING-HORMONE; OLIVER-MCFARLANE; GENE-EXPRESSION; BRAIN-STEM; POL III; DIFFERENTIATION; PTF1A; METHYLTRANSFERASE; ABSENCE; NEURONS |
Files
A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia
(19.9 Mb)
PDF
Licence
http://creativecommons.org/licenses/by/4.0/
Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
Version
VoR
Downloadable Citations
About RVC Repository
Administrator e-mail: publicationsrepos@rvc.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search