PROK2 – Kallmann syndrome

Prokineticin-2 (PROK2) is a secreted ligand for the G protein-coupled receptor PROKR2 and plays a critical role in olfactory bulb development and embryonic migration of gonadotropin-releasing hormone (GnRH) neurons. Loss-of-function variants in PROK2 disrupt the prokineticin signaling pathway, leading to the clinical features of Kallmann syndrome, namely congenital hypogonadotropic hypogonadism and anosmia.

1. Clinical Validity

Autosomal recessive and digenic modes of inheritance are documented for PROK2-related Kallmann syndrome. Thirteen unrelated probands with heterozygous or homozygous PROK2 mutations have been reported, including four distinct missense/frameshift alleles in PLoS Genetics (PMID:17054399), five alleles in a cohort of 170 patients (PMID:18559922), two biallelic cases in sporadic KS (PMID:18285834), and one reversal case with c.163del (p.Ser54_Ile55insTer) (PMID:29022642).

2. Genetic Evidence

Inheritance mode: Autosomal recessive (with reports of digenic/oligogenic heterozygosity). A total of 13 probands harbor PROK2 variants: missense (p.Ala24Pro, p.Cys34Tyr, p.Ile50Met, p.Arg73Cys), frameshift (c.163del (p.Ser54_Ile55insTer)), and nonsense alleles. Homozygous p.Gly100fsX121 was identified in two affected brothers, illustrating segregation in a consanguineous pedigree (PMID:18682503).

3. Functional Evidence

In vitro assays (luciferase and calcium mobilization) demonstrate that all PROK2 mutant peptides except p.Ile50Met exhibit impaired activation of PROKR2, with decreased MAPK signaling and receptor expression (PMID:18559922). Prok2 knockout mice phenocopy the olfactory bulb hypoplasia and GnRH neuron migratory defects seen in human KS (PMID:18559922, PMID:18682503).

4. Conflicting Evidence

Heterozygous PROK2 variants are sometimes found in unaffected carriers and in digenic contexts with PROKR2 or KAL1 mutations, indicating incomplete penetrance and oligogenic inheritance in a subset of patients (PMID:17054399).

5. Integration & Conclusion

Collectively, genetic and experimental data support a loss-of-function mechanism for PROK2 in Kallmann syndrome. Both homozygous and certain heterozygous alleles reduce ligand potency, disrupting GnRH neuronal migration and olfactory development. Variable expressivity highlights the role of genetic modifiers and digenic interactions.

Key Take-home: PROK2 variant screening is recommended in diagnostic panels for Kallmann syndrome, particularly in autosomal recessive pedigrees or when digenic inheritance is suspected.

References

• PLoS Genetics • 2006 • Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PMID:17054399
• The Journal of Clinical Endocrinology & Metabolism • 2008 • Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. PMID:18559922
• European Journal of Human Genetics • 2008 • Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome. PMID:18285834
• The Journal of Clinical Endocrinology & Metabolism • 2008 • Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. PMID:18682503
• Endokrynologia Polska • 2017 • Induction of puberty with human chorionic gonadotropin (hCG) followed by reversal of hypogonadotropic hypogonadism in Kallmann syndrome. PMID:29022642

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