Hietamäki, J;
Gregory, LC;
Ayoub, S;
Iivonen, A-P;
Vaaralahti, K;
Liu, X;
Brandstack, N;
... Raivio, T; + view all
(2020)
Loss-of-function variants in TBC1D32 underlie syndromic hypopituitarism.
The Journal of Clinical Endocrinology & Metabolism
10.1210/clinem/dgaa078.
(In press).
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Abstract
CONTEXT: Congenital pituitary hormone deficiencies with syndromic phenotypes, and/or familial occurrence suggest genetic hypopituitarism; however, in many such patients the underlying molecular basis of the disease remains unknown. OBJECTIVE: To describe patients with syndromic hypopituitarism due to biallelic loss-of-function variants in TBC1D32, a gene implicated in Sonic hedgehog (Shh) signaling. SETTING: Referral center. PATIENTS: A Finnish family of two siblings with panhypopituitarism, absent anterior pituitary, and mild craniofacial dysmorphism, and a Pakistani family with a proband with growth hormone deficiency, anterior pituitary hypoplasia, and developmental delay. INTERVENTIONS: The patients were investigated by whole genome sequencing. Expression profiling of TBC1D32 in human fetal brain was performed through in situ hybridization. Stable and dynamic protein-protein interaction partners of TBC1D32 were investigated in HEK cells followed by mass spectrometry analyses. MAIN OUTCOME MEASURES: Genetic and phenotypic features of patients with biallelic loss-of-function mutations in TBC1D32. RESULTS: The Finnish patients harboured compound heterozygous loss-of-function variants (c.1165_1166dup p.(Gln390Phefs*32), and c.2151del p.(Lys717Asnfs*29)) in TBC1D32; the Pakistani proband carried a known pathogenic homozygous TBC1D32 splice-site variant c.1372+1G>A p.(Arg411_Gly458del), as did a fetus with cleft lip and partial intestinal malrotation from a terminated pregnancy within the same pedigree. TBC1D32 was expressed in the developing hypothalamus, Rathke's pouch and areas of the hindbrain. TBC1D32 interacted with proteins implicated in cilium assembly, Shh signaling, and brain development. CONCLUSIONS: Biallelic TBC1D32 variants underlie syndromic hypopituitarism, and the underlying mechanism may be via disrupted Shh signaling.
| Type: | Article |
|---|---|
| Title: | Loss-of-function variants in TBC1D32 underlie syndromic hypopituitarism |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1210/clinem/dgaa078 |
| Publisher version: | https://doi.org/10.1210/clinem/dgaa078 |
| Language: | English |
| Additional information: | © Endocrine Society 2020. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Sonic hedgehog signaling, TBC1D32, ciliopathy, hypopituitarism, retinal dystrophy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10092096 |
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