Variations in PROKR2, But Not PROK2, Are Associated With Hypopituitarism and Septo-optic Dysplasia

Mark J. McCabe, Carles Gaston-Massuet, Louise C. Gregory, Kyriaki S. Alatzoglou, Vaitsa Tziaferi, Oualid Sbai, Philippe Rondard, Koh-hei Masumoto, Mamoru Nagano, Yasufumi Shigeyoshi, Marija Pfeifer, Tony Hulse, Charles Buchanan, Nelly Pitteloud, Juan-Pedro Martinez-Barbera, Mehul T. Dattani*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    52 Citations (Scopus)

    Abstract

    Context: Loss-of-function mutations in PROK2 and PROKR2 have been implicated in Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism and anosmia. Recent data suggest overlapping phenotypes/genotypes between KS and congenital hypopituitarism (CH), including septo-optic dysplasia (SOD).

    Objective: We screened a cohort of patients with complex forms of CH (n = 422) for mutations in PROK2 and PROKR2.

    Results: We detected 5 PROKR2 variants in 11 patients with SOD/CH: novel p.G371R and previously reported p.A51T, p.R85L, p.L173R, and p.R268C-the latter 3 being known functionally deleterious variants. Surprisingly, 1 patient with SOD was heterozygous for the p.L173R variant, whereas his phenotypically unaffected mother was homozygous for the variant. We sought to clarify the role of PROKR2 in hypothalamopituitary development through analysis of Prokr2(-/-) mice. Interestingly, these revealed predominantly normal hypothalamopituitary development and terminal cell differentiation, with the exception of reduced LH; this was inconsistent with patient phenotypes and more analogous to the healthy mother, although she did not have KS, unlike the Prokr2(-/-) mice.

    Conclusions: The role of PROKR2 in the etiology of CH, SOD, and KS is uncertain, as demonstrated by no clear phenotype-genotype correlation; loss-of-function variants in heterozygosity or homozygosity can be associated with these disorders. However, we report a phenotypically normal parent, homozygous for p.L173R. Our data suggest that the variants identified herein are unlikely to be implicated in isolation in these disorders; other genetic or environmental modifiers may also impact on the etiology. Given the phenotypic variability, genetic counseling may presently be inappropriate.

    Original languageEnglish
    Pages (from-to)E547-E557
    Number of pages11
    JournalJournal of Clinical Endocrinology and Metabolism
    Volume98
    Issue number3
    DOIs
    Publication statusPublished - Mar 2013

    Keywords

    • GONADOTROPIN-RELEASING-HORMONE
    • ENDOTHELIAL GROWTH-FACTOR
    • KALLMANN-SYNDROME
    • SUPRACHIASMATIC NUCLEI
    • OLFACTORY-BULB
    • HYPOGONADOTROPIC HYPOGONADISM
    • PROKINETICIN RECEPTOR-2
    • CLINICAL SPECTRUM
    • MUTATIONS
    • GENES

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