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Single‐nucleotide variants in two Hedgehog genes, SHH and HHIP , as genetic cause of combined pituitary hormone deficiency
Author(s) -
Blanco Darya Gorbenko del,
Graaff Laura C. G.,
Visser Theo J.,
HokkenKoelega Anita C. S.
Publication year - 2013
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/cen.12000
Subject(s) - sonic hedgehog , gene , biology , hedgehog signaling pathway , exon , mutation , genetics , single nucleotide polymorphism , endocrinology , hedgehog , medicine , cancer research , genotype
Summary Objective Combined pituitary hormone deficiency ( CPHD ) is characterized by deficiencies of two or more anterior pituitary hormones. Its genetic cause is unknown in the majority of cases. The Hedgehog (Hh) signalling pathway has been implicated in disorders associated with pituitary development. Mutations in Sonic Hedgehog ( SHH ) have been described in patients with holoprosencephaly (with or without pituitary involvement). Hedgehog interacting protein ( HHIP ) has been associated with variations in adult height in genome wide association studies. We investigated whether mutations in these two genes of the Hh pathway, SHH and HHIP , could result in ′idiopathic′ CPHD . Design/Patients We directly sequenced the coding regions and exon – intron boundaries of SHH and HHIP in 93 CPHD patients of the Dutch HYPOPIT study in whom mutations in the classical CPHD genes PROP 1, POU 1F1, HESX 1, LHX 3 and LHX 4 had been ruled out. We compared the expression of Hh genes in Hep3B transfected cells between wild‐type proteins and mutants. Results We identified three single‐nucleotide variants (p.Ala226Thr, c.1078C>T and c.*8G>T) in SHH . The function of the latter was severely affected in our in vitro assay. In HHIP , we detected a new activating variant c.‐1G>C, which increases HHIP 's inhibiting function on the Hh pathway. Conclusions Our results suggest involvement of the Hedgehog pathway in CPHD . We suggest that both SHH and HHIP are investigated as a second screening in CPHD , after mutations in the classical CPHD genes have been ruled out.