Two Cockayne Syndrome patients with a novel splice site mutation – clinical and metabolic analyses

• Published in: Mechanisms of ageing and development Vol. 175; pp. 7 - 16
• Main Authors: Sanchez-Roman, Ines, Lautrup, Sofie, Aamann, Maria Diget, Neilan, Edward G., Østergaard, John R., Stevnsner, Tinna
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.10.2018
• Subjects: Child, Preschool; Cockayne Syndrome; Cockayne Syndrome - complications; Cockayne Syndrome - diagnosis; Cockayne Syndrome - genetics; Cockayne Syndrome - metabolism; CSB; DNA Helicases - genetics; DNA Mutational Analysis; DNA Repair Enzymes - genetics; Energy Metabolism - genetics; ERCC6; Genetic Predisposition to Disease; Humans; Infant; Magnetic Resonance Imaging; Male; Metabolomics; Metabolomics - methods; Mutation; Phenotype; Poly-ADP-Ribose Binding Proteins - genetics; Premature aging; RNA Splice Sites - genetics; Splice site mutation; Tomography, X-Ray Computed; Metabolomics; Splice site mutation; Premature aging; CSB; ERCC6; Cockayne Syndrome
• ISSN: 0047-6374; 1872-6216
• DOI: 10.1016/j.mad.2018.06.001

•Novel mutation in ERCC6 is affecting splicing of mRNA encoding the CSB protein.•Changes in metabolics in Cockayne Syndrome patient cells with novel mutation in ERCC6.•Increase in glycolytic intermediates and decrease in some in fibroblasts from two Danish CSB patients.•Reduced level of α-ketoglutarate, hydroxyglutarate and certain amino acids in fibroblasts from two Danish CSB patients. 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.