1. Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism
- Author
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Johanna Känsäkoski, Sandy Ayoub, Tiina Laine, Päivi J. Miettinen, Anna-Pauliina Iivonen, Johanna Hietamäki, Xiaonan Liu, Emma Wakeling, Louise C. Gregory, Matti Hero, Mehul T. Dattani, Nina Brandstack, Andrew J Buckton, Kirsi Vaaralahti, Markku Varjosalo, Taneli Raivio, HUS Children and Adolescents, Raivio Group, Children's Hospital, Helsinki University Hospital Area, Medicum, Department of Physiology, STEMM - Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Institute of Biotechnology, Molecular Systems Biology, Helsinki Institute of Life Science HiLIFE, HUS Medical Imaging Center, Department of Diagnostics and Therapeutics, Clinicum, Centre of Excellence in Stem Cell Metabolism, Timo Pyry Juhani Otonkoski / Principal Investigator, Biosciences, and Research Programs Unit
- Subjects
0301 basic medicine ,Proband ,Male ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Hypopituitarism ,Sonic Hedgehog signaling ,Bioinformatics ,Compound heterozygosity ,HORMONE DEFICIENCY ,Biochemistry ,NEGATIVE REGULATION ,0302 clinical medicine ,Endocrinology ,Sonic hedgehog ,Child ,Clinical Research Article ,biology ,CYCLE-RELATED KINASE ,Prognosis ,3. Good health ,Pedigree ,medicine.anatomical_structure ,Phenotype ,Child, Preschool ,FKBP8 ,Female ,TBC1D32 ,AcademicSubjects/MED00250 ,Signal Transduction ,medicine.medical_specialty ,GENES ,Growth hormone deficiency ,03 medical and health sciences ,Anterior pituitary ,Internal medicine ,CILIA ,medicine ,Humans ,retinal dystrophy ,Adaptor Proteins, Signal Transducing ,COMPLEX ,business.industry ,Biochemistry (medical) ,Infant, Newborn ,Infant ,medicine.disease ,Cilium assembly ,Ciliopathy ,030104 developmental biology ,ciliopathy ,3121 General medicine, internal medicine and other clinical medicine ,Mutation ,biology.protein ,PITUITARY-GLAND DEVELOPMENT ,business ,030217 neurology & neurosurgery ,Biomarkers ,Follow-Up Studies - 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.
- Published
- 2020