垂体机能减退
先证者
内分泌学
生物
内科学
外显子组测序
胶质2
垂体前叶
小阴茎
垂体疾病
表型
复合杂合度
遗传学
医学
音猬因子
突变
激素
基因
尿道下裂
作者
Johanna Hietamäki,Louise 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 Dattani,Taneli Raivio
标识
DOI:10.1210/clinem/dgaa078
摘要
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.1372 + 1G > 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI