Two Cockayne Syndrome Patients with a Novel Splice Site Mutation – Clinical and Metabolic Analyses

Publication date: Available online 23 June 2018Source: Mechanisms of Ageing and DevelopmentAuthor(s): Ines Sanchez-Roman, Sofie Lautrup, Maria Diget Aamann, Edward G. Neilan, John R. Østergaard, Tinna StevnsnerABSTRACTCockayne 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 Cockayne Syndrome. 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 no...
Source: Mechanisms of Ageing and Development - Category: Geriatrics Source Type: research