Two Cockayne Syndrome patients with a novel splice site mutation - clinical and metabolic analyses.
Mech Ageing Dev
; 175: 7-16, 2018 10.
Article
em En
| MEDLINE
| ID: mdl-29944916
ABSTRACT
Cockayne Syndrome (CS) is a rare autosomal recessive disorder, which leads to neurodegeneration, growth failure and premature aging. Most of the cases are due to mutations in the ERCC6 gene, which encodes the protein CSB. CSB is involved in several functions including DNA repair and transcription. Here we describe two Danish brothers with CS. Both patients carried a novel splice site mutation (c.2382+2T>G), and a previously described nonsense mutation (c.3259C>T, p.Arg1087X) in a biallelic state. Both patients presented the cardinal features of the disease including microcephaly, congenital cataract and postnatal growth failure. In addition, their fibroblasts were hypersensitive to UV irradiation and exhibited increased superoxide levels in comparison to fibroblasts from healthy age and gender matched individuals. Metabolomic analysis revealed a distinctive metabolic profile in cells from the CS patients compared to control cells. Among others, α-ketoglutarate, hydroxyglutarate and certain amino acids (ornithine, proline and glycine) were reduced in the CS patient fibroblasts, whereas glycolytic intermediates (glucose-6-phosphate and pyruvic acid) and fatty acids (palmitic, stearic and myristic acid) were increased. Our data not only provide additional information to the database of CS mutations, but also point towards targets for potential treatment of this devastating disease.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Síndrome de Cockayne
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DNA Helicases
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Sítios de Splice de RNA
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Enzimas Reparadoras do DNA
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Metabolismo Energético
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Proteínas de Ligação a Poli-ADP-Ribose
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Mutação
Tipo de estudo:
Diagnostic_studies
Limite:
Child, preschool
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Humans
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Infant
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Male
Idioma:
En
Revista:
Mech Ageing Dev
Ano de publicação:
2018
Tipo de documento:
Article