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Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations.


ABSTRACT: 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 [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. 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.

SUBMITTER: Zanette V 

PROVIDER: S-EPMC7577545 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by <i>POLR3A</i> mutations.

Zanette Vanessa V   Reyes Aurelio A   Johnson Mark M   do Valle Daniel D   Robinson Alan J AJ   Monteiro Vaneisse V   Telles Bruno Augusto BA   L R Souza Ricardo R   S F Santos Mara L ML   Benincá Cristiane C   Zeviani Massimo M  

Neurology. Genetics 20201007 6


<h4>Objective</h4>To expand the clinical phenotype of <i>POLR3A</i> mutations by assessing the functional consequences of a missense and a splicing acceptor mutation.<h4>Methods</h4>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 [<sup>1</sup>H]-magnetic  ...[more]

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