PROKR2 – Kallmann Syndrome

Prokineticin receptor 2 (PROKR2; HGNC:15836) is a G-protein-coupled receptor for prokineticin 2. Heterozygous and biallelic PROKR2 variants underlie isolated gonadotropin-releasing hormone (GnRH) deficiency presenting as Kallmann syndrome (PMID:18559922).

Inheritance is primarily autosomal dominant with evidence of oligogenic/digenic contribution. While homozygous loss-of-function alleles cause autosomal recessive KS, most patients carry single PROKR2 variants segregating with disease in multiple families, with at least 19 additional affected relatives reported overall.

Over 50 unrelated KS probands harbour PROKR2 mutations, including missense (e.g., c.337T>C (p.Tyr113His)), nonsense, frameshift, and splice variants. The c.337T>C (p.Tyr113His) change recurs in independent cohorts and is absent from controls (PMID:18559922).

Functional assays demonstrate that most PROKR2 missense variants impair receptor function by reducing Gq-mediated Ca²⁺ mobilization, MAPK activation, or cell surface expression (PMID:18826963). Homozygous frameshift alleles (e.g., p.Gly100fs) abolish signaling and cause recessive KS (PMID:18682503). Animal knockout models recapitulate olfactory and GnRH migration defects.

Incomplete penetrance is observed: phenotypically normal homozygous carriers of p.Leu173Arg and other loss-of-function alleles have been reported in combined pituitary hormone deficiency and septo-optic dysplasia cohorts (PMID:23386640). This suggests additional genetic or environmental modifiers.

Integration of genetic and experimental data supports PROKR2 haploinsufficiency and defective receptor trafficking/signaling as key mechanisms in KS. Although oligogenic interactions complicate inheritance, PROKR2 variant screening enhances diagnostic yield and informs genetic counseling.

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
• Human molecular genetics • 2009 • PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. PMID:18826963
• 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 • 2013 • Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia. PMID:23386640

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