title: A novel mutation in the promoter of RARS2 causes pontocerebellar hypoplasia in two siblings.
abstract: Pontocerebellar hypoplasia (PCH) is characterized by hypoplasia and atrophy of the cerebellum, variable pontine atrophy, microcephaly, severe mental and motor impairments and seizures. Mutations in 11 genes have been reported in 8 out of 10 forms of PCH. Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase gene (RARS2) have been recently associated with PCH type 6, which is characterized by early-onset encephalopathy with signs of oxidative phosphorylation defect. Here we describe the clinical presentation, neuroimaging findings and molecular characterizations of two siblings with a clinical diagnosis of PCH who displayed a novel variant (c.-2A>G) in the 5'-UTR of the RARS2 gene in the homozygous state. This variant was identified through next-generation sequencing testing of a panel of nine genes known to be involved in PCH. Gene expression and functional studies demonstrated that the c.-2A>G sequence change directly leads to a reduced RARS2 messenger RNA expression in the patients by decreasing RARS2 promoter activity, thus providing evidence that mutations in the RARS2 promoter are likely to represent a new causal mechanism of PCH6.
authors: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors: Zejuan
authors: Z
authors: Li
authors: 1] Division of Genetics and Metabolism, Children's National Health System, Washington, DC, USA [2] The George Washington University Medical Center, Washington, DC, USA.
authors: Rhonda
authors: R
authors: Schonberg
authors: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors: Lucia
authors: L
authors: Guidugli
authors: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors: Amy Knight
authors: AK
authors: Johnson
authors: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors: Stephen
authors: S
authors: Arnovitz
authors: Division of Genetics and Metabolism, Children's National Health System, Washington, DC, USA.
authors: Sandra
authors: S
authors: Yang
authors: 1] The George Washington University Medical Center, Washington, DC, USA [2] Division of Neurology, Children's National Health System, Washington, DC, USA.
authors: Joseph
authors: J
authors: Scafidi
authors: 1] Division of Genetics and Metabolism, Children's National Health System, Washington, DC, USA [2] The George Washington University Medical Center, Washington, DC, USA.
authors: Marshall L
authors: ML
authors: Summar
authors: 1] The George Washington University Medical Center, Washington, DC, USA [2] Department of Radiology, Children's National Health System, Washington, DC, USA.
authors: Gilbert
authors: G
authors: Vezina
authors: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors: Soma
authors: S
authors: Das
authors: 1] Division of Genetics and Metabolism, Children's National Health System, Washington, DC, USA [2] The George Washington University Medical Center, Washington, DC, USA.
authors: Kimberly
authors: K
authors: Chapman
authors: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors: Daniela
authors: D
authors: del Gaudio
mesh_terms: D001126:Arginine-tRNA Ligase / Q000235:genetics*; D001483:Base Sequence; D002526:Cerebellar Diseases / Q000175:diagnosis / Q000235:genetics; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017354:Point Mutation; D011401:Promoter Regions, Genetic
chemical_list: D001126:Arginine-tRNA Ligase; C000604250:RARS2 protein, human