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Pellagra-like Syndrome Proves to be a Variant of Xeroderma Pigmentosum-Cockayne Syndrome and Niacin Confers Clinical Benefit
Last modified: 2014-04-03
Abstract
OBJECTIVE: To identify the causal mutation in pellagra-like syndrome and investigate the mechanism by which niacin confers clinical benefit.
BACKGROUND: An extremely rare pellagra-like syndrome (OMIM 260650) has been described in two multiplex Arab families in which extreme skin sensitivity to sun was associated with a multisystem involvement, primarily neurological, and early lethality. The condition was proposed to represent a novel autosomal recessive entity that displayed partial but significant response to niacin supplementation, but the underlying mutation remained unknown for almost three decades.
DESIGN/METHODS: Autozygosity mapping and exome sequencing to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage.
RESULTS: By studying a newly identified relative to the original proband, and another apparently unrelated family, we identified a single disease locus that harbors a novel mutation in ERCC5 thus confirming that the condition is in fact a variant of xeroderma pigmentosum - Cockayne syndrome. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against UV-induced DNA damage in patient’s fibroblasts conferred by niacin treatment.
CONCLUSIONS: 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 Cockayne syndrome. This raises interesting possibilities about the potential therapeutic use of niacin in Cockayne syndrome and the closely related condition of xeroderma pigmentosum.
BACKGROUND: An extremely rare pellagra-like syndrome (OMIM 260650) has been described in two multiplex Arab families in which extreme skin sensitivity to sun was associated with a multisystem involvement, primarily neurological, and early lethality. The condition was proposed to represent a novel autosomal recessive entity that displayed partial but significant response to niacin supplementation, but the underlying mutation remained unknown for almost three decades.
DESIGN/METHODS: Autozygosity mapping and exome sequencing to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage.
RESULTS: By studying a newly identified relative to the original proband, and another apparently unrelated family, we identified a single disease locus that harbors a novel mutation in ERCC5 thus confirming that the condition is in fact a variant of xeroderma pigmentosum - Cockayne syndrome. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against UV-induced DNA damage in patient’s fibroblasts conferred by niacin treatment.
CONCLUSIONS: 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 Cockayne syndrome. This raises interesting possibilities about the potential therapeutic use of niacin in Cockayne syndrome and the closely related condition of xeroderma pigmentosum.
Keywords
Pellagra-like Syndrome ; Xeroderma Pigmentosum-Cockayne Syndrome; Niacin; DNA damage; Autozygosity mapping ; Exome sequencing
References
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