Abstract
To read the full abstract: J Clin Endocrinol Metab. 2020 Feb 15. pii: dgaa078. doi: 10.1210/clinem/dgaa078. PMID: 32060556.
Highlights
Pituitary hormone deficiencies in combination with extra-pituitary manifestations suggest a role for genes involved in the early patterning of the pituitary, such as HESX1, PITX2, OTX2, SOX2, SOX3, LHX3, LHX4, GLI2, and FGF8, that form a complex cascade culminating in the formation of midline anterior brain and craniofacial structures [1,2,3,4,5,6]
Our results show that the patients carried biallelic loss-of-function variants in TBC1D32, a gene implicated in ciliary function and sonic hedgehog signaling [10,11]
Biallelic TBC1D32 variants have been described in one male patient with severe facial and ocular phenotypes, microcephaly, post-axial polydactyly and central nervous system (CNS) abnormalities including the absence of the pituitary gland with subsequent panhypopituitarism [19]
Summary
To describe patients with syndromic hypopituitarism due to biallelic loss-oft function variants in TBC1D32, a gene implicated in Sonic hedgehog (Shh) signaling. ip SETTING Referral center cr PATIENTS A Finnish family of two siblings with panhypopituitarism, absent anterior s pituitary, and mild craniofacial dysmorphism, and a Pakistani family with a proband with u growth hormone deficiency, anterior pituitary hypoplasia, and developmental delay. n INTERVENTIONS The patients were investigated by whole genome sequencing. a Expression profiling of TBC1D32 in human fetal brain was performed through in situ M hybridization. To describe patients with syndromic hypopituitarism due to biallelic loss-oft function variants in TBC1D32, a gene implicated in Sonic hedgehog (Shh) signaling. A Expression profiling of TBC1D32 in human fetal brain was performed through in situ M hybridization. Stable and dynamic protein-protein interaction partners of TBC1D32 were d investigated in HEK cells followed by mass spectrometry analyses. Te MAIN OUTCOME MEASURES Genetic and phenotypic features of patients with biallelic p loss-of-function mutations in TBC1D32. E RESULTS The Finnish patients harboured compound heterozygous loss-of-function variants c (c.1165_1166dup p.(Gln390Phefs*32), and c.2151del p.(Lys717Asnfs*29)) in TBC1D32; the Ac 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 interacted with proteins implicated in cilium assembly, Shh signaling, and brain development
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