The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism. (9th December 2014)

• Record Type: Journal Article
• Authors: Gregory, L.C.; Gaston‐Massuet, C.; Andoniadou, C.L.; Carreno, G.; Webb, E.A.; Kelberman, D.; McCabe, M.J.; Panagiotakopoulos, L.; Saldanha, J.W.; Spoudeas, H.A.; Torpiano, J.; Rossi, M.; Raine, J.; Canham, N.; Martinez‐Barbera, J.P.; Dattani, M.T.
• Is Part Of: Clinical endocrinology. Volume 82:Number 5(2015:May)
• Page Start: 728
• Page End: 738
• Publication Date: 2014-12-09
• Subjects: Endocrinology -- Periodicals; 616.4005
• DOI: 10.1111/cen.12637
• Languages: English
• ISSNs: 0300-0664

Abstract

<abstract abstract-type="main" id="cen12637-abs-0001"> <title>Summary</title> <sec id="cen12637-sec-0001" sec-type="section"> <title>Introduction</title> <p>The Gli family of zinc finger (GLI) transcription factors mediates the sonic hedgehog signalling pathway (HH) essential for CNS, early pituitary and ventral forebrain development in mice. Human mutations in this pathway have been described in patients with holoprosencephaly (HPE), isolated congenital hypopituitarism (CH) and cranial/midline facial abnormalities. Mutations in <italic>Sonic hedgehog</italic> (<italic>SHH</italic>) have been associated with HPE but not CH, despite murine studies indicating involvement in pituitary development.</p> </sec> <sec id="cen12637-sec-0002" sec-type="section"> <title>Objectives/Methods</title> <p>We aimed to establish the role of the HH pathway in the aetiology of hypothalamo‐pituitary disorders by screening our cohort of patients with midline defects and/or CH for mutations in <italic>SHH</italic>, <italic> GLI2</italic>, <italic> Shh brain enhancer 2</italic> (<italic>SBE2</italic>) and <italic>growth‐arrest specific 1</italic> (<italic>GAS1</italic>).</p> </sec> <sec id="cen12637-sec-0003" sec-type="section"> <title>Results</title> <p>Two variants and a deletion of <italic>GLI2</italic> were identified in three patients. A novel variant at a highly conserved residue in the zinc finger DNA‐binding domain, c.1552G > A [pE518K], was identified in a patient with growth hormone deficiency and low normal free T4. A nonsynonymous variant, c.2159G > A [p.R720H], was identified in a patient with a short neck, cleft palate and hypogonadotrophic hypogonadism. A 26·6 Mb deletion, 2q12·3‐q21·3, encompassing <italic>GLI2</italic> and 77 other genes, was identified in a patient with short stature and impaired growth. Human embryonic expression studies and molecular characterisation of the GLI2 mutant p.E518K support the potential pathogenicity of <italic>GLI2</italic> mutations. No mutations were identified in <italic>GAS1</italic> or <italic>SBE2</italic>. A novel <italic>SHH</italic> variant, c.1295T>A [p.I432N], was identified in two siblings with variable midline defects but normal pituitary function.</p> </sec> <sec id="cen12637-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Our data suggest that mutations in <italic>SHH</italic>, <italic> GAS1</italic> and <italic>SBE2</italic> are not associated with hypopituitarism, although <italic>GLI2</italic> is an important candidate for CH.</p> </sec> </abstract>