title: Pellagra-like condition is xeroderma pigmentosum/Cockayne syndrome complex and niacin confers clinical benefit.
abstract: An extremely rare pellagra-like condition has been described, which was partially responsive to niacin and associated with a multisystem involvement. The condition was proposed to represent a novel autosomal recessive entity but the underlying mutation remained unknown for almost three decades. The objective of this study was to identify the causal mutation in the pellagra-like condition and investigate the mechanism by which niacin confers clinical benefit. Autozygosity mapping and exome sequencing were used to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage. We identified a single disease locus that harbors a novel mutation in ERCC5, thus confirming that the condition is in fact xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against ultraviolet-induced DNA damage in patient fibroblasts conferred by niacin treatment. Our findings show the power of exome sequencing in reassigning previously described novel clinical entities, and suggest a mechanism for the dermatological response to niacin in patients with XP/CS complex. This raises interesting possibilities about the potential therapeutic use of niacin in XP.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: H
authors.initials: H
authors.lastname: Hijazi
authors.forename: M A
authors.initials: MA
authors.lastname: Salih
authors.forename: M H A
authors.initials: MH
authors.lastname: Hamad
authors.forename: H H
authors.initials: HH
authors.lastname: Hassan
authors.forename: S B M
authors.initials: SB
authors.lastname: Salih
authors.forename: K A
authors.initials: KA
authors.lastname: Mohamed
authors.forename: M M
authors.initials: MM
authors.lastname: Mukhtar
authors.forename: Z A
authors.initials: ZA
authors.lastname: Karrar
authors.forename: S
authors.initials: S
authors.lastname: Ansari
authors.forename: N
authors.initials: N
authors.lastname: Ibrahim
authors.forename: F S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D003057:Cockayne Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D059472:Exome / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D009525:Niacin / Q000494:pharmacology / Q000627:therapeutic use*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010383:Pellagra / Q000473:pathology*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*; D014983:Xeroderma Pigmentosum / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D004268:DNA-Binding Proteins; D004720:Endonucleases; D009525:Niacin; D009687:Nuclear Proteins; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5
keywords: Cockayne; DNA damage; exome; niacin; pellagra-like; xeroderma pigmentosum