A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia
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
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
View: Text | PDF
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

×

Figure 1

Exome sequencing identifies a PRDM13 mutation in 3 patients from 2 Maltese pedigrees.

Options: View larger image (or click on image) Download as PowerPoint
Exome sequencing identifies a PRDM13 mutation in 3 patients from 2 Malte...
(A) Pedigree 1 with 1 affected male (VI.3) (patient 1) and 1 affected female (VI.4) (patient 2) with a syndrome associated with HH and cerebellar hypoplasia carrying a homozygous PRDM13 mutation. Circles denote females; squares denote males; black square denotes affected male, and black circle denotes affected female; a dot in the middle of a shape indicates a heterozygous carrier; arrow indicates the proband. (B–D) (B and C) Axial slices on CT scan of the brain showing cerebellar hypoplasia in patient 1 compared with a normal CT scan from an unrelated individual (D). Arrows in B and C demonstrate hypoplastic cerebellar lobes as compared with those in the control scan (D). The pons (P) is hypoplastic compared with the scan in D, as is the cerebellar vermis (asterisk). Partial voluming from the occipital lobes above the tentorium is seen (O). (D) CT scan showing normal cerebellar lobes (arrows), a normal cerebellar vermis (asterisk), and a normal pons (P). (E) Diagram of PRDM13 transcript (NM_021620.4) showing the deletion found in patients at the intron 3/exon 4 border, which is predicted to affect splicing and to form a truncated PRDM13 protein. (F) Electropherograms of patients 1 and 2 and their unaffected parents (pedigree 1) showing the c.398-3_407delCAGGGGAGGAGCG deletion homozygous in the 2 patients and heterozygous in the healthy parents. Aff, affected.