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Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations
OBJECTIVE: To expand the clinical phenotype of POLR3A mutations by assessing the functional consequences of a missense and a splicing acceptor mutation. METHODS: We performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generaliz...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Wolters Kluwer
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577545/ https://www.ncbi.nlm.nih.gov/pubmed/33134517 http://dx.doi.org/10.1212/NXG.0000000000000521 |
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author | Zanette, Vanessa Reyes, Aurelio Johnson, Mark do Valle, Daniel Robinson, Alan J. Monteiro, Vaneisse Telles, Bruno Augusto L.R. Souza, Ricardo S.F. Santos, Mara L Benincá, Cristiane Zeviani, Massimo |
author_facet | Zanette, Vanessa Reyes, Aurelio Johnson, Mark do Valle, Daniel Robinson, Alan J. Monteiro, Vaneisse Telles, Bruno Augusto L.R. Souza, Ricardo S.F. Santos, Mara L Benincá, Cristiane Zeviani, Massimo |
author_sort | Zanette, Vanessa |
collection | PubMed |
description | OBJECTIVE: To expand the clinical phenotype of POLR3A mutations by assessing the functional consequences of a missense and a splicing acceptor mutation. METHODS: We performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia atrophy and presence of lactate and lipid peaks by [(1)H]-magnetic resonance spectroscopy. Expression levels of Pol III target genes were measured by quantitative real-time (qRT)-PCR to study the pathogenicity of the biallelic mutations in patient fibroblasts. RESULTS: The patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in POLR3A, the gene coding for the catalytic subunit of RNA polymerase III (Pol III). Aberrant splicing was observed for the c.1771-6C>G mutation. Decreased RNA expression levels of Pol III targets (HNRNPH2, ubiquitin B, lactotransferrin, and HSP90AA1) were observed in patient fibroblasts with rescue to normal levels by overexpression of the wild-type protein but not by the p.Val1241Met variant. CONCLUSIONS: Mutations in the POLR3A gene cause POLR3A-related hypomyelinating leukodystrophy with or without oligodontia or hypogonadotropic hypogonadism (HLD7, OMIM: 607694) and neonatal progeroid syndrome (OMIM: 264090), both with high phenotypic variability. We demonstrated the pathogenicity of c.1771-6C>G and c.3721G>A mutations causing an early-onset disorder. The phenotype of our patient expands the clinical presentation of POLR3A-related mutations and suggests a new classification that we propose designating as Neurodevelopmental Disorder with Regression, Abnormal Movements, and Increased Lactate. |
format | Online Article Text |
id | pubmed-7577545 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Wolters Kluwer |
record_format | MEDLINE/PubMed |
spelling | pubmed-75775452020-10-30 Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations Zanette, Vanessa Reyes, Aurelio Johnson, Mark do Valle, Daniel Robinson, Alan J. Monteiro, Vaneisse Telles, Bruno Augusto L.R. Souza, Ricardo S.F. Santos, Mara L Benincá, Cristiane Zeviani, Massimo Neurol Genet Article OBJECTIVE: To expand the clinical phenotype of POLR3A mutations by assessing the functional consequences of a missense and a splicing acceptor mutation. METHODS: We performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia atrophy and presence of lactate and lipid peaks by [(1)H]-magnetic resonance spectroscopy. Expression levels of Pol III target genes were measured by quantitative real-time (qRT)-PCR to study the pathogenicity of the biallelic mutations in patient fibroblasts. RESULTS: The patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in POLR3A, the gene coding for the catalytic subunit of RNA polymerase III (Pol III). Aberrant splicing was observed for the c.1771-6C>G mutation. Decreased RNA expression levels of Pol III targets (HNRNPH2, ubiquitin B, lactotransferrin, and HSP90AA1) were observed in patient fibroblasts with rescue to normal levels by overexpression of the wild-type protein but not by the p.Val1241Met variant. CONCLUSIONS: Mutations in the POLR3A gene cause POLR3A-related hypomyelinating leukodystrophy with or without oligodontia or hypogonadotropic hypogonadism (HLD7, OMIM: 607694) and neonatal progeroid syndrome (OMIM: 264090), both with high phenotypic variability. We demonstrated the pathogenicity of c.1771-6C>G and c.3721G>A mutations causing an early-onset disorder. The phenotype of our patient expands the clinical presentation of POLR3A-related mutations and suggests a new classification that we propose designating as Neurodevelopmental Disorder with Regression, Abnormal Movements, and Increased Lactate. Wolters Kluwer 2020-10-07 /pmc/articles/PMC7577545/ /pubmed/33134517 http://dx.doi.org/10.1212/NXG.0000000000000521 Text en Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Article Zanette, Vanessa Reyes, Aurelio Johnson, Mark do Valle, Daniel Robinson, Alan J. Monteiro, Vaneisse Telles, Bruno Augusto L.R. Souza, Ricardo S.F. Santos, Mara L Benincá, Cristiane Zeviani, Massimo Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations |
title | Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations |
title_full | Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations |
title_fullStr | Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations |
title_full_unstemmed | Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations |
title_short | Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations |
title_sort | neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by polr3a mutations |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577545/ https://www.ncbi.nlm.nih.gov/pubmed/33134517 http://dx.doi.org/10.1212/NXG.0000000000000521 |
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