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 2 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.1372ā
+ā
1Gā
>ā
A p.(Arg411_Gly458del), as did a fetus with a 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.
|
Authors | Johanna Hietamäki, Louise C Gregory, Sandy Ayoub, Anna-Pauliina Iivonen, Kirsi Vaaralahti, Xiaonan Liu, Nina Brandstack, Andrew J Buckton, Tiina Laine, Johanna Känsäkoski, Matti Hero, Päivi J Miettinen, Markku Varjosalo, Emma Wakeling, Mehul T Dattani, Taneli Raivio |
Journal | The Journal of clinical endocrinology and metabolism
(J Clin Endocrinol Metab)
Vol. 105
Issue 6
(06 01 2020)
ISSN: 1945-7197 [Electronic] United States |
PMID | 32060556
(Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | © Endocrine Society 2020. |
Chemical References |
- Adaptor Proteins, Signal Transducing
- Biomarkers
- TBC1D32 protein, human
|
Topics |
- Adaptor Proteins, Signal Transducing
(genetics)
- Biomarkers
(analysis)
- Child
- Child, Preschool
- Female
- Follow-Up Studies
- Humans
- Hypopituitarism
(etiology, pathology)
- Infant
- Infant, Newborn
- Male
- Mutation
- Pedigree
- Phenotype
- Prognosis
- Signal Transduction
|