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Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism
- Source :
- Annals of neurology 90(1), 143-158 (2021). doi:10.1002/ana.26127, Dipòsit Digital de Documents de la UAB, Universitat Autònoma de Barcelona, Ann. Neurol. 90, 143-158 (2021), Annals of neurology
- Publication Year :
- 2021
- Publisher :
- Wiley-Blackwell, 2021.
-
Abstract
- Objective Precursors of peptide hormones undergo posttranslational modifications within the trans-Golgi network (TGN). Dysfunction of proteins involved at different steps of this process cause several complex syndromes affecting the central nervous system (CNS). We aimed to clarify the genetic cause in a group of patients characterized by hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy. Methods Whole exome sequencing (WES) was performed in seven individuals of six unrelated families with these features. Postmortem histopathological and HID1 expression analysis of brain tissue and pituitary gland were conducted in one patient. Functional consequences of the homozygous HID1 variant p.R433W were investigated by Seahorse XF Assay in fibroblasts of two patients. Results Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in all patients. Post mortem examination confirmed cerebral atrophy with enlarged lateral ventricles. Markedly reduced expression of pituitary hormones was found in pituitary gland tissue. Colocalization of HID1 protein with the TGN was not altered in fibroblasts of patients compared to controls, while the extracellular acidification rate (ECAR) upon stimulation with potassium chloride was significantly reduced in patient fibroblasts compared to controls. Interpretation Our findings indicate that mutations in HID1 cause an early infantile encephalopathy with hypopituitarism as the leading presentation, and expand the list of syndromic CNS diseases caused by interference of TGN function. This article is protected by copyright. All rights reserved.
- Subjects :
- 0301 basic medicine
Male
Pituitary gland
Pathology
medicine.medical_specialty
Central nervous system
genetics [Epilepsy]
Hypopituitarism
Peptide hormone
Article
pathology [Epilepsy]
03 medical and health sciences
Epilepsy
Young Adult
0302 clinical medicine
Atrophy
Exome Sequencing
Medicine
Humans
ddc:610
genetics [Hypopituitarism]
Exome sequencing
Alleles
Cerebral atrophy
Brain Diseases
business.industry
genetics [Brain Diseases]
pathology [Brain Diseases]
Infant
medicine.disease
pathology [Pituitary Gland]
ddc
030104 developmental biology
medicine.anatomical_structure
Neurology
Pituitary Gland
Child, Preschool
Female
Neurology (clinical)
pathology [Hypopituitarism]
business
General Economics, Econometrics and Finance
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 15318249
- Database :
- OpenAIRE
- Journal :
- Annals of neurology 90(1), 143-158 (2021). doi:10.1002/ana.26127, Dipòsit Digital de Documents de la UAB, Universitat Autònoma de Barcelona, Ann. Neurol. 90, 143-158 (2021), Annals of neurology
- Accession number :
- edsair.doi.dedup.....3330af47383d2432390544a36ec919b7