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...

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Bibliographic Details
Published in:	The Journal of clinical investigation 2021-12, Vol.131 (24), p.1-16
Main Authors:	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 Jj, Rajabali, Sakina H, Riegman, Kimberley Lh, De Martini, Lisa B, Chaya, Taro, Robinson, Iain Caf, Furukawa, Takahisa, Cariboni, Anna, Basson, M Albert, Dattani, Mehul T
Format:	Article
Language:	eng
Subjects:	Age Analysis Animals Ataxia Brain Brain diseases Care and treatment Cell fate Cerebellum Cerebellum - abnormalities Cerebellum - enzymology Chromatin Development and progression Developmental Disabilities - enzymology Developmental Disabilities - genetics Disease Models, Animal Ectopic expression Females GABA Gene expression Gene mutations Genetic aspects Genetic disorders Glutamatergic transmission Health aspects Histone-Lysine N-Methyltransferase - genetics Histone-Lysine N-Methyltransferase - metabolism Humans Hypogonadism Hypogonadism - enzymology Hypogonadism - genetics Hypoplasia Hypothalamus Hypothalamus - enzymology Intellectual disabilities Kiss1 protein Mice Mice, Mutant Strains Mutation Nervous System Malformations - enzymology Nervous System Malformations - genetics Neurogenesis Neurons Neurons - enzymology Neuropeptides Patients Pax2 protein Pediatrics Progenitor cells Puberty Scoliosis Spinal cord Surgery Testes Testosterone Tlx3 protein Transcription factors Transcription Factors - genetics Transcription Factors - metabolism Ventricle Ventricular zone γ-Aminobutyric acid
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Summary:	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.
ISSN:	1558-8238 0021-9738 1558-8238