PROKR2 – Septo-optic Dysplasia

Heterozygous variants in PROKR2 have been reported in patients with Septo-optic Dysplasia, often in the context of combined pituitary hormone deficiency. A single case report described a novel missense variant c.742C>T (p.Arg248Trp) in a female with CPHD, morning glory syndrome and pituitary dysplasia (1 proband) (PMID:25678757). In a cohort of 422 patients with complex congenital hypopituitarism, 11 individuals harbored five distinct PROKR2 missense variants including p.Ala51Thr, p.Arg85Leu, p.Leu173Arg, p.Arg268Cys and p.Gly371Arg (11 probands) (PMID:23386640). A separate screen of 103 CPHD/SOD patients uncovered heterozygous loss-of-function variants in 4 individuals (4 probands) (PMID:22319038). In total, 16 unrelated probands carry PROKR2 missense variants in septo-optic dysplasia (PMID:25678757; PMID:23386640; PMID:22319038). Segregation is incomplete and expressivity variable, with no additional clearly affected relatives identified.

Functional assays demonstrate that many PROKR2 variants impair G protein-coupling and receptor trafficking. The p.Arg248Trp change is predicted deleterious by SIFT and PolyPhen-2 and variants in intracellular loop regions show reduced calcium mobilization and MAPK activation. Murine Prokr2⁻/⁻ models exhibit largely normal pituitary development, suggesting species-specific effects. Together, the genetic and experimental data support a limited association of heterozygous PROKR2 variants with septo-optic dysplasia, likely requiring additional genetic or environmental modifiers. Key take-home: PROKR2 sequencing can aid diagnosis in SOD but results should be interpreted in the context of incomplete penetrance and variable phenotype.

References

• Clinical Pediatric Endocrinology : Case Reports and Clinical Investigations • 2015 • Combined pituitary hormone deficiency with unique pituitary dysplasia and morning glory syndrome related to a heterozygous PROKR2 mutation. PMID:25678757
• The Journal of Clinical Endocrinology and Metabolism • 2013 • Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia. PMID:23386640
• The Journal of Clinical Endocrinology and Metabolism • 2012 • Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia. PMID:22319038

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