Kraemer KH, Patronas NJ, Schiffmann R, Brooks BP, Tamura D, DiGiovanna JJXeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience 145:1388-1396

DNA Repair Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Building 37 Room 4002 MSC 4258, Bethesda, MD 20892-4258, USA.
Neuroscience (Impact Factor: 3.36). 05/2007; 145(4):1388-96. DOI: 10.1016/j.neuroscience.2006.12.020
Source: PubMed


Patients with the rare genetic disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS) have defects in DNA nucleotide excision repair (NER). The NER pathway involves at least 28 genes. Three NER genes are also part of the basal transcription factor, TFIIH. Mutations in 11 NER genes have been associated with clinical diseases with at least eight overlapping phenotypes. The clinical features of these patients have some similarities but also have marked differences. NER is involved in protection against sunlight-induced DNA damage. While XP patients have 1000-fold increase in susceptibility to skin cancer, TTD and CS patients have normal skin cancer risk. Several of the genes involved in NER also affect somatic growth and development. Some patients have short stature and immature sexual development. TTD patients have sulfur deficient brittle hair. Progressive sensorineural deafness is an early feature of XP and CS. Many of these clinical diseases are associated with developmental delay and progressive neurological degeneration. The main neuropathology of XP is a primary neuronal degeneration. In contrast, CS and TTD patients have reduced myelination of the brain. These complex neurological abnormalities are not related to sunlight exposure but may be caused by developmental defects as well as faulty repair of DNA damage to neuronal cells induced by oxidative metabolism or other endogenous processes.

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    • "Xeroderma pigmentosum (XP) is an autosomal recessive cancer prone disease characterized by sensitivity to ultraviolet rays (UVR). XP patients are consequently predisposed to develop skin and eyes cancers [1]. This disease is caused by inherited mutations in DNA repair genes encoding proteins that protect cells from UV-induced damage. "
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    ABSTRACT: Xeroderma pigmentosum Variant (XP-V) form is characterized by a late onset of skin symptoms. Our aim is the clinical and genetic investigations of XP-V Tunisian patients in order to develop a simple tool for early diagnosis. We investigated 16 suspected XP patients belonging to ten consanguineous families. Analysis of the POLH gene was performed by linkage analysis, long range PCR, and sequencing. Genetic analysis showed linkage to the POLH gene with a founder haplotype in all affected patients. Long range PCR of exon 9 to exon 11 showed a 3926 bp deletion compared to control individuals. Sequence analysis demonstrates that this deletion has occurred between two Alu-Sq2 repetitive sequences in the same orientation, respectively, in introns 9 and 10. We suggest that this mutation POLH NG_009252.1: g.36847_40771del3925 is caused by an equal crossover event that occurred between two homologous chromosomes at meiosis. These results allowed us to develop a simple test based on a simple PCR in order to screen suspected XP-V patients. In Tunisia, the prevalence of XP-V group seems to be underestimated and clinical diagnosis is usually later. Cascade screening of this founder mutation by PCR in regions with high frequency of XP provides a rapid and cost-effective tool for early diagnosis of XP-V in Tunisia and North Africa.
    BioMed Research International 05/2014; 2014:256245. DOI:10.1155/2014/256245 · 1.58 Impact Factor
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    • "The manifestation of the disorder includes severe sunburns when exposed to even minute sunlight (Bradford et al., 2011; Feller et al., 2010), freckles on the face, irritation and pain in the eyes, corneal ulcerations and increased risk of skin cancer (Bradford et al., 2011). A number of cancers like cancers on face, lips, scalp, eyes, tip of the tongue and eyelids have been associated with XP (Kraemer et al., 2007; Liu and Chen, 2006). XP not only affects the eyes or skin but also induces neurological abnormalities such as loss in hearing ability, seizures and deprived movement and speech (Bradford et al., 2011; Robbins et al., 1974). "
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    ABSTRACT: Xeroderma pigmentosum (XP) is a rare genetic skin disorder caused due to the extreme sensitivity for ultraviolet (UV) radiations. On its exposure, DNA acquires damages leading to skin and often neurological abnormalities. The DNA repair implicated in fixing UV-induced damages is NER and mutations in genes involved in NER and TLS form the basis of XP. The analyses of such mutations are vital for understanding XP and involved cancer genetics to facilitate the identification of crucial biomarkers and anticancer therapeutics. We detected the deleterious nsSNPs and examined them at structure-level by altering the structure, estimating secondary structure, solvent accessibility and performing site specific analysis. Crucial phosphorylation sites were also identified for their role in the disorder. These mutational and structural analyses offer valuable insight to the fundamental association of genetic mutations with phenotypic variations in XP and will assist experimental biologists to evaluate the mutations and their impact on genome.
    Gene 04/2014; 543(1). DOI:10.1016/j.gene.2014.03.057 · 2.14 Impact Factor
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    • "Moreover, the rate of age-related deterioration and functional decline varies within every individual in a tissue-specific manner [7-12]. In humans, lifespan ranges from less than 10 years for the severe progeria patients [13, 14] to over 100 years for centenarians. Many pro-aging factors are likely controlled to some extent by genetic variation [2, 15]. "
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    ABSTRACT: In the next decades the elderly population will increase dramatically, demanding appropriate solutions in health care and aging research focusing on healthy aging to prevent high burdens and costs in health care. For this, research targeting tissue-specific and individual aging is paramount to make the necessary progression in aging research. In a recently published study we have attempted to make a step interpreting aging data on chronological as well as pathological scale. For this, we sampled five major tissues at regular time intervals during the entire C57BL/6J murine lifespan from a controlled in vivo aging study, measured the whole transcriptome and incorporated temporal as well as physical health aspects into the analyses. In total, we used 18 different age-related pathological parameters and transcriptomic profiles of liver, kidney, spleen, lung and brain and created a database that can now be used for a broad systems biology approach. In our study, we focused on the dynamics of biological processes during chronological aging and the comparison between chronological and pathology-related aging.
    Aging 10/2013; 5(10). · 6.43 Impact Factor
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