King's College London

Research portal

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

Research output: Contribution to journalArticlepeer-review

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

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

King's Authors

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.

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454