|
|
Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome) |
|---|---|
| Author: | Rahikkala, Elisa1,2; Myllykoski, Matti3,4; Hinttala, Reetta1,3; |
| Organizations: |
1PEDEGO Research Unit and Medical Research Centre Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland 2Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland 3Biocenter Oulu, University of Oulu, Oulu, Finland
4Faculty of Biochemistry and Molecular Medicine, Oulu Centre for Cell-Matrix Research, University of Oulu, Oulu, Finland
5Department of Children and Adolescents, Division of Paediatric Neurology, Oulu University Hospital, Oulu, Finland 6Kaiser Franz Josef Hospital with G.v. Preyer Children’s Hospital, Department of Pediatrics, Vienna, Austria 7Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands 8Neuromuscular Research Department, Medical University of Vienna, Centre for Anatomy and Cell Biology, Vienna, Austria 9Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA 10The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA 11Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland 12Texas Children’s Hospital, Houston, TX, USA 13Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 14Northern Finland Laboratory Centre NordLab and Medical Research Centre, Oulu 15University Hospital and University of Oulu, Oulu, Finland 16Department of Pathology, Oulu University Hospital, Oulu, Finland 17Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA 18Department of Neurology, Massachusetts General Hospital, Boston, MA, USA 19Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki and Haartman Institute, Helsinki, Finland 20Baylor Genetics, Houston, TX, 77021, USA |
| Format: | article |
| Version: | published version |
| Access: | open |
| Online Access: | PDF Full Text (PDF, 0.7 MB) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe202002256430 |
| Language: | English |
| Published: |
Springer Nature,
2019
|
| Publish Date: | 2020-02-25 |
| Description: |
AbstractPurpose: A new syndrome with hypotonia, intellectual disability, and eye abnormalities (HIDEA) was previously described in a large consanguineous family. Linkage analysis identified the recessive disease locus, and genome sequencing yielded three candidate genes with potentially pathogenic biallelic variants: transketolase (TKT), transmembrane prolyl 4-hydroxylase (P4HTM), and ubiquitin specific peptidase 4 (USP4). However, the causative gene remained elusive. Methods: International collaboration and exome sequencing were used to identify new patients with HIDEA and biallelic, potentially pathogenic, P4HTM variants. Segregation analysis was performed using Sanger sequencing. P4H-TM wild-type and variant constructs without the transmembrane region were overexpressed in insect cells and analyzed using sodium dodecyl sulfate–polyacrylamide gel electrophoresis and western blot. Results: Five different homozygous or compound heterozygous pathogenic P4HTM gene variants were identified in six new and six previously published patients presenting with HIDEA. Hypoventilation, obstructive and central sleep apnea, and dysautonomia were identified as novel features associated with the phenotype. Characterization of three of the P4H-TM variants demonstrated yielding insoluble protein products and, thus, loss-of-function. Conclusions: Biallelic loss-of-function P4HTM variants were shown to cause HIDEA syndrome. Our findings enable diagnosis of the condition, and highlight the importance of assessing the need for noninvasive ventilatory support in patients. see all
|
| Series: |
Genetics in medicine |
| ISSN: | 1098-3600 |
| ISSN-E: | 1530-0366 |
| ISSN-L: | 1098-3600 |
| Volume: | 21 |
| Pages: | 2355 - 2363 |
| DOI: | 10.1038/s41436-019-0503-4 |
| OADOI: | https://oadoi.org/10.1038/s41436-019-0503-4 |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
3111 Biomedicine |
| Subjects: | |
| Funding: |
This study was supported by the Academy of Finland Grants 266719 and 308009, the S. Jusélius Foundation, the Emil Aaltonen Foundation, and the Jane and Aatos Erkko Foundation to P.K. |
| Academy of Finland Grant Number: |
266719 308009 |
| Detailed Information: |
266719 (Academy of Finland Funding decision) 308009 (Academy of Finland Funding decision) |
| Copyright information: |
© The Author(s) 2019. This article is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. If you remix, transform, or build upon this article or a part thereof, you must distribute your contributions under the same license as the original. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/. |
|
https://creativecommons.org/licenses/by-nc-sa/4.0/ |