Phenotypic and genotypic landscape of PROKR2 in neuroendocrine disorders

Abstract

Prokineticin receptor 2 (PROKR2) encodes for a G-protein-coupled receptor that can bind PROK1 and PROK2. Mice lacking Prokr2 have been shown to present abnormal olfactory bulb formation as well as defects in GnRH neuron migration. Patients carrying mutations in PROKR2 typically present hypogonadotropic hypogonadism, anosmia/hyposmia or Kallmann Syndrome. More recently variants in PROKR2 have been linked to several other endocrine disorders. In particular, several patients with pituitary disorders have been reported, ranging from mild phenotypes, such as isolated growth hormone deficiency, to more severe ones, such as septo-optic dysplasia. Here we summarize the changing landscape of PROKR2-related disease, the variants reported to date, and discuss their origin, classification and functional assessment.

Keywords: functional assay; genetic diagnosis; hypogonadotropic hypogonadism; kallmann syndrome; pituitary.

Figure 1

(A) Flow diagram showing the search and selection of studies. (B) Relative frequency of phenotypes in patients harboring PROKR2 pathogenic or likely pathogenic variants. (C) Reported PROKR2 variants. Pie charts next to each variant denote the percentage of patients carrying that variant that presented each phenotype. Each variant is coloured according to ACMG classification, where P = red, LP = orange, VUS = purple, LB = light green, B = dark green. Dotted underline means the variant was reported at least once as compound heterozygous and a full underline that it was reported at least once as homozygous. Gray boxes indicate transmembrane domains.