Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations
| Autor: | Ricardo L.R. Souza, Cristiane Benincá, Bruno Augusto Telles, Massimo Zeviani, Vanessa Zanette, Mara Lúcia Schmitz Ferreira Santos, Mark H. Johnson, Daniel Almeida do Valle, Alan J. Robinson, Vaneisse Monteiro, Aurelio Reyes |
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| Přispěvatelé: | Zanette, Vanessa [0000-0001-7933-860X], Reyes, Aurelio [0000-0003-4480-2286], Robinson, Alan J [0000-0001-9943-0059], Monteiro, Vaneisse [0000-0003-4062-4638], Telles, Bruno Augusto [0000-0002-1177-8091], Zeviani, Massimo [0000-0002-9067-5508], Apollo - University of Cambridge Repository |
| Rok vydání: | 2020 |
| Předmět: |
32 Biomedical and Clinical Sciences
Biology Neurodegenerative Compound heterozygosity medicine.disease_cause Article 3105 Genetics Neonatal Progeroid Syndrome 3102 Bioinformatics and Computational Biology Neurodevelopmental disorder Rare Diseases medicine Genetics Missense mutation 2.1 Biological and endogenous factors Gene Genetics (clinical) 2 Aetiology Mutation FOS: Clinical medicine Neurosciences medicine.disease Molecular biology Hypotonia FOS: Biological sciences RNA splicing Neurology (clinical) medicine.symptom 31 Biological Sciences Biotechnology |
| Zdroj: | Neurology: Genetics article-version (Version of Record) 3 |
| Popis: | ObjectiveTo expand the clinical phenotype of POLR3A mutations by assessing the functional consequences of a missense and a splicing acceptor mutation.MethodsWe 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 [1H]-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.ResultsThe 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.ConclusionsMutations 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. |
| Databáze: | OpenAIRE |
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