Cargando…

Recessive PRDM13 Mutations Result in Hypogonadotropic Hypogonadism and Cerebellar Hypoplasia

PRDM13 (PR Domain containing 13) is a putative chromatin modifier and transcriptional regulator that functions downstream of the transcription factor PTF1A. Here, we report a novel, recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar...

Descripción completa

Detalles Bibliográficos
Autores principales: Oleari, Roberto, Whittaker, Danielle, Gregory, Louise Cheryl, Albert, Basson, Cariboni, Anna Maria, Dattani, Mehul Tulsidas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090531/
http://dx.doi.org/10.1210/jendso/bvab048.1122
_version_ 1783687305969532928
author Oleari, Roberto
Whittaker, Danielle
Gregory, Louise Cheryl
Albert, Basson
Cariboni, Anna Maria
Dattani, Mehul Tulsidas
author_facet Oleari, Roberto
Whittaker, Danielle
Gregory, Louise Cheryl
Albert, Basson
Cariboni, Anna Maria
Dattani, Mehul Tulsidas
author_sort Oleari, Roberto
collection PubMed
description PRDM13 (PR Domain containing 13) is a putative chromatin modifier and transcriptional regulator that functions downstream of the transcription factor PTF1A. Here, we report a novel, recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty with hypogonadotropic hypogonadism (HH). We investigated the development of hypothalamic neurons and the cerebellum in mice homozygous for a Prdm13 mutant allele. Cerebellar hypoplasia was evident, but male gonadal development appeared unaffected in these mutants. As PTF1A has been linked to early GABAergic neuronal cell fate regulation in the spinal cord, we examined GABAergic neuron progenitor development in the hypothalamus and cerebellum. A significant reduction in the number of Kisspeptin neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone was observed. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate during neurodevelopment, providing a mechanistic explanation for the co-occurrence of HH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted regulation of Kiss1 neurons to CHH in humans.
format Online
Article
Text
id pubmed-8090531
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-80905312021-05-05 Recessive PRDM13 Mutations Result in Hypogonadotropic Hypogonadism and Cerebellar Hypoplasia Oleari, Roberto Whittaker, Danielle Gregory, Louise Cheryl Albert, Basson Cariboni, Anna Maria Dattani, Mehul Tulsidas J Endocr Soc Neuroendocrinology and Pituitary PRDM13 (PR Domain containing 13) is a putative chromatin modifier and transcriptional regulator that functions downstream of the transcription factor PTF1A. Here, we report a novel, recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty with hypogonadotropic hypogonadism (HH). We investigated the development of hypothalamic neurons and the cerebellum in mice homozygous for a Prdm13 mutant allele. Cerebellar hypoplasia was evident, but male gonadal development appeared unaffected in these mutants. As PTF1A has been linked to early GABAergic neuronal cell fate regulation in the spinal cord, we examined GABAergic neuron progenitor development in the hypothalamus and cerebellum. A significant reduction in the number of Kisspeptin neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone was observed. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate during neurodevelopment, providing a mechanistic explanation for the co-occurrence of HH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted regulation of Kiss1 neurons to CHH in humans. Oxford University Press 2021-05-03 /pmc/articles/PMC8090531/ http://dx.doi.org/10.1210/jendso/bvab048.1122 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Neuroendocrinology and Pituitary
Oleari, Roberto
Whittaker, Danielle
Gregory, Louise Cheryl
Albert, Basson
Cariboni, Anna Maria
Dattani, Mehul Tulsidas
Recessive PRDM13 Mutations Result in Hypogonadotropic Hypogonadism and Cerebellar Hypoplasia
title Recessive PRDM13 Mutations Result in Hypogonadotropic Hypogonadism and Cerebellar Hypoplasia
title_full Recessive PRDM13 Mutations Result in Hypogonadotropic Hypogonadism and Cerebellar Hypoplasia
title_fullStr Recessive PRDM13 Mutations Result in Hypogonadotropic Hypogonadism and Cerebellar Hypoplasia
title_full_unstemmed Recessive PRDM13 Mutations Result in Hypogonadotropic Hypogonadism and Cerebellar Hypoplasia
title_short Recessive PRDM13 Mutations Result in Hypogonadotropic Hypogonadism and Cerebellar Hypoplasia
title_sort recessive prdm13 mutations result in hypogonadotropic hypogonadism and cerebellar hypoplasia
topic Neuroendocrinology and Pituitary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090531/
http://dx.doi.org/10.1210/jendso/bvab048.1122
work_keys_str_mv AT oleariroberto recessiveprdm13mutationsresultinhypogonadotropichypogonadismandcerebellarhypoplasia
AT whittakerdanielle recessiveprdm13mutationsresultinhypogonadotropichypogonadismandcerebellarhypoplasia
AT gregorylouisecheryl recessiveprdm13mutationsresultinhypogonadotropichypogonadismandcerebellarhypoplasia
AT albertbasson recessiveprdm13mutationsresultinhypogonadotropichypogonadismandcerebellarhypoplasia
AT cariboniannamaria recessiveprdm13mutationsresultinhypogonadotropichypogonadismandcerebellarhypoplasia
AT dattanimehultulsidas recessiveprdm13mutationsresultinhypogonadotropichypogonadismandcerebellarhypoplasia