A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia
Danielle E. Whittaker, … , M. Albert Basson, Mehul T. Dattani
Danielle E. Whittaker, … , M. Albert Basson, Mehul T. Dattani
Published November 2, 2021
Citation Information: J Clin Invest. 2021;131(24):e141587. https://doi.org/10.1172/JCI141587.
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Research Article Development Endocrinology

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

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+ 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.

Authors

Danielle E. Whittaker, Roberto Oleari, Louise C. Gregory, Polona Le Quesne-Stabej, Hywel J. Williams, GOSgene, John G. Torpiano, Nancy Formosa, Mario J. Cachia, Daniel Field, Antonella Lettieri, Louise A. Ocaka, Alyssa J.J. Paganoni, Sakina H. Rajabali, Kimberley L.H. Riegman, Lisa B. De Martini, Taro Chaya, Iain C.A.F. Robinson, Takahisa Furukawa, Anna Cariboni, M. Albert Basson, Mehul T. Dattani

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Figure 6

PRDM13 is a critical regulator of GABAergic cell fate in the cerebellum.

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PRDM13 is a critical regulator of GABAergic cell fate in the cerebellum....
(A) PAX2 cell counts in Prdm13+/+ and Prdm13–/– cerebella. Note the reduction in PAX2+ cells in the vermis and hemisphere of Prdm13–/– mice at E16.5 and P0 (n = 4 per genotype). (B and C) Immunohistochemistry of sagittal cerebella sections at E14.5 of Prdm13+/+ and Prdm13–/– mice using antibodies to PAX2 and TLX3 to label GABAergic interneurons and glutamatergic progenitors, respectively. Note the marked reduction in PAX2+ cells in Prdm13–/– mice (C) (pink asterisks) and the concomitant increase in TLX3+ cells (C) (green arrowheads). (D) Quantification of PAX2+ and TLX3+ cells is shown at E14.5. Note the decrease in PAX2+ cells, accompanied by an increase in TLX3+ neurons. (E and F) Neurogranin+ Golgi cell counts in Prdm13+/+ and Prdm13–/– vermis (E) and hemispheres (F) at P21. Note the similar number of Golgi cells between genotypes. (G) Quantification of parvalbumin+ MLIs in the cerebellum at P21. Note the reduction in MLIs in the vermis and hemispheres of Prdm13–/– mice. (H and I) Lobule-specific MLI cell counts in the vermis and hemispheres at P21. Note the significant reduction in MLIs across all vermis and hemisphere lobules of Prdm13–/– cerebella. (J–M) Immunohistochemistry of sagittal cerebella sections at P21 of Prdm13+/+ and Prdm13–/– mice using antibodies to parvalbumin to label MLIs. Note the reduction in parvalbumin+ cells in the vermis (K) and hemispheres (M) of Prdm13–/– mice. (N–Q) Golgi-Cox–stained sagittal sections of adult Prdm13+/+ and Prdm13–/– cerebella. Note that the morphology of the basket (N and O) and stellate cells (P and Q) is consistent between Prdm13+/+ and Prdm13–/– mice. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed unpaired Student’s t test. NG, neurogranin; CI, Crus I; CII, Crus II. Scale bars: 300 μm (B); 100 μm (J and N).