Recessive PRDM13 Mutations Result in Hypogonadotropic Hypogonadism and Cerebellar Hypoplasia

Abstract PRDM13 (PR Domain containing 13) is a putative chromatin modifier and transcriptional regulator that functions downstream of the transcription factor PTF1A. Here, we report novel, recessive syndrome associated with mutation. Patients exhibited intellectual disability, ataxia cerebellar hypoplasia, scoliosis delayed puberty hypogonadotropic hypogonadism (HH). We investigated development hypothalamic neurons cerebellum in mice homozygous for Prdm13 mutant allele. Cerebellar hypoplasia was evident, but male gonadal appeared unaffected these mutants. As PTF1A has been linked to early GABAergic neuronal cell fate regulation spinal cord, examined neuron progenitor hypothalamus cerebellum. A significant reduction number Kisspeptin PAX2+ progenitors emerging from ventricular zone observed. The latter accompanied by ectopic expression glutamatergic lineage marker TLX3. Together, findings identify as critical during neurodevelopment, providing mechanistic explanation co-occurrence HH this syndrome. To our knowledge, first evidence linking disrupted Kiss1 CHH humans.