Celia’s encephalopathy and c.974dupG in BSCL2 gene: a hidden change in a known variant
| Autor: | Angels García-Cazorla, Melissa Crocker, Miguel Garrido-Pumar, Antonio Rodríguez-Núñez, Rosario Domingo-Jiménez, Julián Álvarez-Escudero, Ana I. Castro, Pablo Aguiar, Álvaro Ruibal, Antía Fernández-Pombo, Rebecca J. Brown, David Araújo-Vilar, Sofía Sánchez-Iglesias, Mar O'Callaghan, Alejandra Darling |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
DNA Complementary BSCL2 Encephalopathy Bioinformatics Article Congenital generalized lipodystrophy 03 medical and health sciences Cellular and Molecular Neuroscience Exon 0302 clinical medicine Fatal Outcome Lipodystrophy Congenital Generalized GTP-Binding Protein gamma Subunits Genetics medicine Humans Child Index case Genetics (clinical) Brain Diseases business.industry Homozygote Genetic Variation Neurodegenerative Diseases Exons Sequence Analysis DNA Fibroblasts medicine.disease Alternative Splicing 030104 developmental biology Phenotype Child Preschool Myoclonic epilepsy Female Lipodystrophy business Asymptomatic carrier 030217 neurology & neurosurgery |
| Zdroj: | Neurogenetics |
| Popis: | Celia’s encephalopathy (Progressive Encephalopathy with/without Lipodystrophy, PELD) is a childhood neurodegenerative disorder with a fatal prognosis before the age of 10, due to the variant c.985C>T in the BSCL2 gene that causes a cryptic splicing site leading to skipping of exon 7. For years, different authors have reported cases of congenital generalized lipodystrophy due to the variant c.974dupG in BSCL2 associated with neurological manifestations of variable severity, although some of them clearly superimposable to PELD. AIM: To identify the molecular mechanisms responsible for these neurological alterations in two patients with c.974dupG. SUBJECTS AND METHODS: Clinical characterization, biochemistry and neuroimaging studies of two girls carrying this variant. In silico analysis, PCR amplification and BSCL2 cDNA sequencing. BSCL2-201 transcript expression, which lacks exon 7, by qPCR in fibroblasts from the index case, from a healthy child as a control and from two patients with PELD, and in leukocytes from the index case and her parents. RESULTS: One of the children presented with a severe encephalopathy including a picture of intellectual deficiency, severe language impairment, myoclonic epilepsy and lipodystrophy as described in PELD, dying at 9 years and 9 months of age. The other 2-year-old patient showed incipient signs of neurological involvement. In silico and cDNA sequencing studies showed that variant c.974dupG gives rise to skipping of exon 7. The expression of BSCL2-201 in fibroblasts was significantly higher in the index case than in the healthy child, although less than in the case with homozygous PELD due to c.985C>T variant. The expression of this transcript was approximately half in the healthy carrier parents of this patient. CONCLUSIONS: The c.974dupG variant leads to the skipping of exon 7 of the BSCL2 gene, and is responsible for a variant of Celia’s encephalopathy, with variable phenotypic expression. |
| Databáze: | OpenAIRE |
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