A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia
| Autor: | Iain C.A.F. Robinson, Roberto Oleari, Sakina Rajabali, Hywel Williams, Takahisa Furukawa, Mario J. Cachia, Kimberley L. H. Riegman, Mehul T. Dattani, Daniel Field, Alyssa Paganoni, Louise C. Gregory, M. Albert Basson, Lisa Benedetta De Martini, Anna Cariboni, Antonella Lettieri, Polona Le Quesne Stabej, John Torpiano, Taro Chaya, Nancy Formosa, Danielle E. Whittaker, Louise Ocaka |
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| Rok vydání: | 2021 |
| Předmět: |
Cerebellum
medicine.medical_specialty Ataxia Developmental Disabilities Neurodevelopment Hypothalamus Development Biology Nervous System Malformations Mice Endocrinology Kisspeptin Internal medicine medicine Animals Humans Neuroendocrine regulation Neurons Hypogonadism Neurogenesis Histone-Lysine N-Methyltransferase General Medicine medicine.disease Mice Mutant Strains Disease Models Animal medicine.anatomical_structure nervous system Mutation Ectopic expression Cerebellar hypoplasia (non-human) Neuron Congenital Hypogonadotropic Hypogonadism medicine.symptom Research Article Genetic diseases Transcription Factors |
| Zdroj: | The Journal of Clinical Investigation |
| ISSN: | 1558-8238 |
| DOI: | 10.1172/jci141587 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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