Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2019 Mar;90(3):449-456.
doi: 10.1111/cen.13914. Epub 2019 Jan 7.

Novel GLI2 mutations identified in patients with Combined Pituitary Hormone Deficiency (CPHD): Evidence for a pathogenic effect by functional characterization

Deepak Babu  1 , Antonella Fanelli  1 , Simona Mellone  1 , Ranjith Muniswamy  1 , Malgorzata Wasniewska  2 , Flavia Prodam  3 , Antonella Petri  3 , Simonetta Bellone  3 , Maria Carolina Salerno  4 , Mara Giordano  1
Affiliations
Case Reports

Novel GLI2 mutations identified in patients with Combined Pituitary Hormone Deficiency (CPHD): Evidence for a pathogenic effect by functional characterization

Deepak Babu et al. Clin Endocrinol (Oxf). 2019 Mar.

Abstract

Context: The Gli-family of zinc-finger transcription factors regulates the Sonic Hedgehog (Shh) signalling pathway that plays a key role in early pituitary and ventral forebrain development. Heterozygous GLI2 loss of function mutations in humans have been reported in holoprosencephaly (HPE), HPE-like phenotypes associated with pituitary anomalies and combined pituitary hormone deficiency with or without other extra-pituitary findings.

Objective: The aim of this study was the search for GLI2 mutations in a cohort of Italian CPHD patients and the assessment of a pathogenic role for the identified variants through in vitro studies.

Patients: One hundred forty-five unrelated CPHD patients diagnosed with or without extra-pituitary manifestations were recruited from different Italian centres.

Methods: The GLI2 mutation screening was carried out through direct sequencing of all the 13 exons and intron-exon boundaries. Luciferase reporter assays were performed to evaluate the role of the detected missense variants.

Results: Five different novel heterozygous non-synonymous GLI2 variants were identified in five patients. The mutations were three missense (p.Pro386Leu, p.Tyr575His, p.Ala593Val), one frameshift (p.Val1111Glyfs*19) and one nonsense (p.Arg1226X). The latter two mutants are likely pathogenic since they lead to a truncated protein. The in vitro functional study of the plasmids bearing two of the three missense variants (namely p.Tyr575His and p.Ala593Val) revealed a significant reduction in transcriptional activity.

Conclusion: In conclusion, the analysis of GLI2 in individuals with CPHD led to the identification of five variations with a likely negative impact on the GLI2 protein, confirming that GLI2 is an important causative gene in CPHD. The functional in vitro study analysis performed on the missense variations were useful to strengthen the hypothesis of pathogenicity.

Keywords: CPHD; GLI2 gene.

PubMed Disclaimer

Supplementary concepts