cholecalciferol and Xeroderma-Pigmentosum

Xeroderma pigmentosum (XP) is a rare genodermatosis predisposing to skin cancers. Autoimmune diseases related to XP are rarely discussed in the literature. Type 1 diabetes (T1D) has been associated with other genodermatoses like Cockayne syndrome, but it has never been described in XP. In the present study, we report the rare occurrence of T1D in XP patients. Five XP patients belonging to 4 consanguineous families originating from different regions of Tunisia were investigated. Their ages ranged between 8 and 18 years. All the patients had a severe hypovitaminosis D. All the patients had positive GAD antibody levels, and 4 of them had familial history of other autoimmune diseases. The spectrum of XP was variable in all the patients, with dermatological and neurological symptoms, and the occurrence of some cancers. Various hypotheses have been proposed to explain this association, among of which we cite the role of immunomodulation and down-regulation of ATP-dependent DNA excision repair protein genes, implying that impaired DNA repair may contribute to the development of some autoimmune diseases. Vitamin D3 deficiency secondary to sun protective measures was found in all patients and thus may play a role in increasing T1D risk in these patients.

Topics: Adenosine Triphosphate; Adolescent; Child; Cholecalciferol; Diabetes Mellitus, Type 1; DNA; Humans; Xeroderma Pigmentosum

XPD (ERCC2) is a DNA helicase involved in nucleotide excision repair and in transcription as a structural bridge tying the transcription factor IIH (TFIIH) core with the cdk-activating kinase complex, which phosphorylates nuclear receptors. Mutations in XPD are associated with several different phenotypes, including trichothiodystrophy (TTD), with sulfur-deficient brittle hair, bone defects, and developmental abnormalities without skin cancer, xeroderma pigmentosum (XP), with pigmentary abnormalities and increased skin cancer, or XP/TTD with combined features, including skin cancer. We describe the varied clinical features and mutations in nine patients examined at the National Institutes of Health who were compound heterozygotes for XPD mutations but had different clinical phenotypes: four TTD, three XP, and two combined XP/TTD. We studied TFIIH-dependent transactivation by nuclear receptor for vitamin D (VDR) and thyroid in cells from these patients. The vitamin D stimulation ratio of CYP24 and osteopontin was associated with specific pairs of mutations (reduced in 5, elevated in 1) but not correlated with distinct clinical phenotypes. Thyroid receptor stimulation ratio for KLF9 was not significantly different from normal. XPD mutations frequently were associated with abnormal VDR stimulation in compound heterozygote patients with TTD, XP, or XP/TTD.

Topics: Adolescent; Adult; Cells, Cultured; Child; Cholecalciferol; DNA Repair; Female; Fibroblasts; Gene Expression; Humans; Kruppel-Like Transcription Factors; Male; Mutation; Osteopontin; Receptors, Calcitriol; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; Steroid Hydroxylases; Transcription Factor TFIIH; Transcriptional Activation; Trichothiodystrophy Syndromes; Triiodothyronine; Vitamin D3 24-Hydroxylase; Vitamins; Xeroderma Pigmentosum; Xeroderma Pigmentosum Group D Protein