PROKR2 – Hypogonadotropic Hypogonadism

PROKR2 encodes the G-protein-coupled prokineticin receptor 2, whose loss-of-function (LoF) mutations underlie both anosmic (Kallmann syndrome) and normosmic forms of congenital hypogonadotropic hypogonadism (MONDO_0018555). Clinical validity is classified as Strong, based on over 30 unrelated probands harboring heterozygous or homozygous PROKR2 variants and consistent functional concordance across multiple studies.

Inheritance of PROKR2-related hypogonadotropic hypogonadism follows an autosomal recessive pattern with frequent incomplete penetrance and oligogenic modifiers. In a cohort of 170 Kallmann syndrome and 154 normosmic IHH patients, 11 carried heterozygous PROKR2 variants (PMID:18559922). A Brazilian series of 107 idiopathic HH patients identified 6 individuals with PROKR2 LoF alleles (PMID:18682503), and a separate screen of 246 central hypogonadism cases found variants in 16 patients (6.5%) (PMID:24276467). One recurrent variant is c.1069C>T (p.Arg357Trp).

Segregation data are limited by variable expressivity; no additional affected relatives beyond probands have been systematically documented. In silico and in vitro case series demonstrated deleterious effects on receptor expression and signaling, but asymptomatic carriers in multiple pedigrees indicate the contribution of additional genetic or environmental modifiers.

The phenotypic spectrum spans failure of puberty, infertility, and anosmia (HP:0000458), often accompanied by variable reproductive features from partial to complete GnRH deficiency (HP:0000044). Reproductive phenotypes may reverse after therapy discontinuation in rare cases.

Functional studies reveal that PROKR2 variants impair Gq-mediated calcium mobilization, MAPK-ERK activation, and/or cAMP signaling depending on the allele. Trafficking-defective mutants (e.g., p.Pro290Ser) can be rescued by chemical chaperones, and biased signaling mutants selectively disrupt G-protein coupling, corroborating a LoF mechanism.

Despite robust genetic and functional evidence, incomplete penetrance, oligogenic inheritance and asymptomatic homozygotes complicate interpretation. No studies have refuted the role of PROKR2 in IHH, but the requirement for additional hits warrants comprehensive genetic screening in clinical diagnostics.

Key Take-home: PROKR2 LoF variants are strongly implicated in congenital hypogonadotropic hypogonadism; targeted genetic and functional assays inform diagnosis, guide genetic counseling, and highlight the need to consider oligogenic contributions.

References

• The Journal of Clinical Endocrinology and Metabolism • 2008 • Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. PMID:18559922
• The Journal of Clinical Endocrinology and Metabolism • 2008 • Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. PMID:18682503
• The Journal of Clinical Endocrinology and Metabolism • 2014 • Germline prokineticin receptor 2 (PROKR2) variants associated with central hypogonadism cause differential modulation of distinct intracellular pathways. PMID:24276467

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