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 3

Prdm13 loss affects Kiss1 expression and Kiss1 neuron development.

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Prdm13 loss affects Kiss1 expression and Kiss1 neuron development. (A) ...
(A) In situ hybridization on coronal adult WT male mice brain sections to detect Prdm13 expression in the Arc and DM nuclei of the hypothalamus, indicated by black arrowheads. (B) qRT-PCR analysis for Npvf and Kiss1 transcripts in the hypothalamus of Prdm13+/+ and Prdm13–/– male mice. ΔΔCq was calculated relative to control samples using Cq threshold values normalized to the housekeeping gene Gapdh. Note the significant decrease of Kiss1 levels in mutants. *P < 0.05, 2-tailed unpaired Student’s t test. (C) qRT-PCR analysis for Gad1 transcripts in the hypothalamus of Prdm13+/+ and Prdm13–/– from both sexes. ΔΔCq was calculated relative to control samples using Cq threshold values that were normalized to the housekeeping gene Gapdh. Note the significant decrease of Gad1 levels in mutants. *P < 0.05, 2-tailed unpaired Student’s t test. (D) In situ hybridization on coronal sections from the Arc nucleus level from Prdm13+/+ and Prdm13–/– male mice, detecting Kiss1 transcripts. Note the reduction in Kiss1 expression in the mutants compared with WT controls, where open arrowheads indicate complete absence of expression. (E and F) In situ hybridization on coronal sections detecting Prdm13/PRDM13 expression in the developing mouse hypothalamus at E12.5 and E14.5 (E) and developing human hypothalamus at CS23 (F). mRNA transcripts are indicated by the arrowheads. The sense probe showed negative staining (first 2 images from the left). (G) In situ hybridization on coronal sections from E14.5 mouse embryo to detect Kiss1 expression in Prdm13+/+ and Prdm13–/–. Black arrowheads indicate examples of Kiss1-expressing cells; note the absence of Kiss1 neurons in mutants (open arrowheads). Areas within marked rectangles are shown in high magnification in adjacent images. Scale bars: 500 μm (A, E, and F, low magnification), 250 μm (A, E, and F, high magnification; D and G). LH, lateral hypothalamus; VMH, ventromedial hypothalamus; AH, anterior hypothalamus; TH, tuberal hypothalamus.