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Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4
BACKGROUND: Thiamine metabolism dysfunction syndrome 4 (THMD4, OMIM #613710) is an autosomal recessive inherited disease caused by the deficiency of SLC25A19 that encodes the mitochondrial thiamine pyrophosphate (TPP) transporter. This disorder is characterized by bilateral striatal degradation and...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480130/ https://www.ncbi.nlm.nih.gov/pubmed/34587972 http://dx.doi.org/10.1186/s13023-021-02028-4 |
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author | Chen, Yuanying Fang, Boliang Hu, Xuyun Guo, Ruolan Guo, Jun Fang, Kenan Ni, Jingwen Li, Wei Qian, Suyun Hao, Chanjuan |
author_facet | Chen, Yuanying Fang, Boliang Hu, Xuyun Guo, Ruolan Guo, Jun Fang, Kenan Ni, Jingwen Li, Wei Qian, Suyun Hao, Chanjuan |
author_sort | Chen, Yuanying |
collection | PubMed |
description | BACKGROUND: Thiamine metabolism dysfunction syndrome 4 (THMD4, OMIM #613710) is an autosomal recessive inherited disease caused by the deficiency of SLC25A19 that encodes the mitochondrial thiamine pyrophosphate (TPP) transporter. This disorder is characterized by bilateral striatal degradation and progressive polyneuropathy with the onset of fever of unknown origin. The limited number of reported cases and lack of functional annotation of related gene variants continue to limit diagnosis. RESULTS: We report three cases of encephalopathy from two unrelated pedigrees with basal ganglia signal changes after fever of unknown origin. To distinguish this from other types of encephalopathy, such as acute necrotizing encephalopathy, exome sequencing was performed, and four novel heterozygous variations, namely, c.169G>A (p.Ala57Thr), c.383C>T (p.Ala128Val), c.76G>A (p.Gly26Arg), and c.745T>A (p.Phe249Ile), were identified in SLC25A19. All variants were confirmed using Sanger sequencing. To determine the pathogenicity of these variants, functional studies were performed. We found that mitochondrial TPP levels were significantly decreased in the presence of SLC25A19 variants, indicating that TPP transport activities of mutated SLC25A19 proteins were impaired. Thus, combining clinical phenotype, genetic analysis, and functional studies, these variants were deemed as likely pathogenic. CONCLUSIONS: Exome sequencing analysis enables molecular diagnosis as well as provides potential etiology. Further studies will enable the elucidation of SLC25A19 protein function. Our investigation supplied key molecular evidence for the precise diagnosis of and clinical decision-making for a rare disease. |
format | Online Article Text |
id | pubmed-8480130 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-84801302021-09-30 Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4 Chen, Yuanying Fang, Boliang Hu, Xuyun Guo, Ruolan Guo, Jun Fang, Kenan Ni, Jingwen Li, Wei Qian, Suyun Hao, Chanjuan Orphanet J Rare Dis Research BACKGROUND: Thiamine metabolism dysfunction syndrome 4 (THMD4, OMIM #613710) is an autosomal recessive inherited disease caused by the deficiency of SLC25A19 that encodes the mitochondrial thiamine pyrophosphate (TPP) transporter. This disorder is characterized by bilateral striatal degradation and progressive polyneuropathy with the onset of fever of unknown origin. The limited number of reported cases and lack of functional annotation of related gene variants continue to limit diagnosis. RESULTS: We report three cases of encephalopathy from two unrelated pedigrees with basal ganglia signal changes after fever of unknown origin. To distinguish this from other types of encephalopathy, such as acute necrotizing encephalopathy, exome sequencing was performed, and four novel heterozygous variations, namely, c.169G>A (p.Ala57Thr), c.383C>T (p.Ala128Val), c.76G>A (p.Gly26Arg), and c.745T>A (p.Phe249Ile), were identified in SLC25A19. All variants were confirmed using Sanger sequencing. To determine the pathogenicity of these variants, functional studies were performed. We found that mitochondrial TPP levels were significantly decreased in the presence of SLC25A19 variants, indicating that TPP transport activities of mutated SLC25A19 proteins were impaired. Thus, combining clinical phenotype, genetic analysis, and functional studies, these variants were deemed as likely pathogenic. CONCLUSIONS: Exome sequencing analysis enables molecular diagnosis as well as provides potential etiology. Further studies will enable the elucidation of SLC25A19 protein function. Our investigation supplied key molecular evidence for the precise diagnosis of and clinical decision-making for a rare disease. BioMed Central 2021-09-29 /pmc/articles/PMC8480130/ /pubmed/34587972 http://dx.doi.org/10.1186/s13023-021-02028-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Chen, Yuanying Fang, Boliang Hu, Xuyun Guo, Ruolan Guo, Jun Fang, Kenan Ni, Jingwen Li, Wei Qian, Suyun Hao, Chanjuan Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4 |
title | Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4 |
title_full | Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4 |
title_fullStr | Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4 |
title_full_unstemmed | Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4 |
title_short | Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4 |
title_sort | identification and functional analysis of novel slc25a19 variants causing thiamine metabolism dysfunction syndrome 4 |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480130/ https://www.ncbi.nlm.nih.gov/pubmed/34587972 http://dx.doi.org/10.1186/s13023-021-02028-4 |
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