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A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia
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 ass...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8670848/ https://www.ncbi.nlm.nih.gov/pubmed/34730112 http://dx.doi.org/10.1172/JCI141587 |
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author | Whittaker, Danielle E. Oleari, Roberto Gregory, Louise C. Le Quesne-Stabej, Polona Williams, Hywel J. Torpiano, John G. Formosa, Nancy Cachia, Mario J. Field, Daniel Lettieri, Antonella Ocaka, Louise A. Paganoni, Alyssa J.J. Rajabali, Sakina H. Riegman, Kimberley L.H. De Martini, Lisa B. Chaya, Taro Robinson, Iain C.A.F. Furukawa, Takahisa Cariboni, Anna Basson, M. Albert Dattani, Mehul T. |
author_facet | Whittaker, Danielle E. Oleari, Roberto Gregory, Louise C. Le Quesne-Stabej, Polona Williams, Hywel J. Torpiano, John G. Formosa, Nancy Cachia, Mario J. Field, Daniel Lettieri, Antonella Ocaka, Louise A. Paganoni, Alyssa J.J. Rajabali, Sakina H. Riegman, Kimberley L.H. De Martini, Lisa B. Chaya, Taro Robinson, Iain C.A.F. Furukawa, Takahisa Cariboni, Anna Basson, M. Albert Dattani, Mehul T. |
author_sort | Whittaker, Danielle E. |
collection | PubMed |
description | 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(+) 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. |
format | Online Article Text |
id | pubmed-8670848 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-86708482021-12-16 A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia Whittaker, Danielle E. Oleari, Roberto Gregory, Louise C. Le Quesne-Stabej, Polona Williams, Hywel J. Torpiano, John G. Formosa, Nancy Cachia, Mario J. Field, Daniel Lettieri, Antonella Ocaka, Louise A. Paganoni, Alyssa J.J. Rajabali, Sakina H. Riegman, Kimberley L.H. De Martini, Lisa B. Chaya, Taro Robinson, Iain C.A.F. Furukawa, Takahisa Cariboni, Anna Basson, M. Albert Dattani, Mehul T. J Clin Invest Research Article 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(+) 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. American Society for Clinical Investigation 2021-12-15 2021-12-15 /pmc/articles/PMC8670848/ /pubmed/34730112 http://dx.doi.org/10.1172/JCI141587 Text en © 2021 Whittaker et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Whittaker, Danielle E. Oleari, Roberto Gregory, Louise C. Le Quesne-Stabej, Polona Williams, Hywel J. Torpiano, John G. Formosa, Nancy Cachia, Mario J. Field, Daniel Lettieri, Antonella Ocaka, Louise A. Paganoni, Alyssa J.J. Rajabali, Sakina H. Riegman, Kimberley L.H. De Martini, Lisa B. Chaya, Taro Robinson, Iain C.A.F. Furukawa, Takahisa Cariboni, Anna Basson, M. Albert Dattani, Mehul T. A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia |
title | A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia |
title_full | A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia |
title_fullStr | A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia |
title_full_unstemmed | A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia |
title_short | A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia |
title_sort | recessive prdm13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8670848/ https://www.ncbi.nlm.nih.gov/pubmed/34730112 http://dx.doi.org/10.1172/JCI141587 |
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