We completed a follow-up report on all 106 XP patients we examined at the NIH Clinical Center since 1971. There was a 10000-fold increase in non-melanoma skin cancer (NMSC) and a 2000-fold increase in melanoma skin cancer in XP patients under age 20. The 9 year median age of diagnosis of first NMSC was significantly younger than the 22 year median age of melanoma - a relative reversal from the general population suggesting different mechanisms of carcinogenesis between NMSC and melanoma. The median age at death of XP patients with neurodegeneration (29 years) was significantly younger than XP patients without neurodegeneration (37 years). This 39 year study indicates a major role for DNA repair genes in the etiology of skin cancer and neurodegeneration. We analyzed hearing function of all XP patients admitted to NIH from 1971 to 2012. We found that audiograms can serve as predictors of patients that will develop progressive neurological degeneration. In collaboration with ophalmologists of the NEI we published a summary of the eye abnormalities in the XP patients examined at the NIH from 1964 to 2011. This highlights the role of DNA repair in protection from sun damage. We have established several hundred carefully documented cell lines and contributed them to cell banks for use of the general scientific community. Our laboratory has become a major center in the US for basic, clinical and translational expertise concerning DNA repair related disorders. We have now identified mutations in all 8 DNA nucleotide excision repair (NER) genes (XPA, XPB, XPC, XPD, XPE, XPF, XPG, and TTDA) and in the error-prone polymerase, pol eta in more than 150 XP and TTD families. In a study of 16 XP-C families we found that most of the XP-C patients had mutations leading to premature stop codons. We found low levels of XPC mRNA in XPC patients while their obligate heterozygote parents had an intermediate level of XPC mRNA between the patients and the normal controls. We found two XP-C families from Turkey that had severe or mild disease that correlated with mutations in two different splice lariat branchpoints (LBP). These LBP mutations resulted in no measurable XPC mRNA or a low (3%) level of XPC mRNA, respectively. This indicates that a) low levels of normal XPC mRNA may provide some protection against cancer and b) reduced levels may increase cancer risk (e.g. potential risk to heterozygotes).We found a wide spectrum of mutations in pol eta in cells from 10 XP variant families in America, Europe and Asia. We are continuing to compare the genotype to the clinical features of XP patients and to characterize the progressive neurologic degeneration that occurs in some XP patients because it may be a model for more common neurodegenerative disorders. In contrast to the profound environmental influence on XP, TTD is a disease of altered development. We performed a comprehensive literature review and identified reports of 112 TTD cases. We found a wide variety of clinical symptoms in many organ systems including an unsuspected 20-fold increase in mortality in children under age 10 years primarily due to infections. We documented significant increased frequency of complications in pregnancies of TTD affected fetuses compared to pregnancies carrying their unaffected siblings and to the general population. More than 80% of these pregnancies had one or more complications. The TTD affected neonates had high frequency of abnormalities including low birth weight, cataracts and cryptorchidism. This date provides evidence of DNA repair gene function in human fetal growth and pregnancy possibly by altering the development of the placenta. We found that these severe pregnancy and prenatal development complications were present only in mothers with TTD affected children, and not with their unaffected children or in mothers with XP affected children. This is an important finding since the TTD affected children and the XP affected children have different mutations in the same gene (XPD) which is involved in both DNA repair and transcription. Using localized UV irradiation we were able to show a consistent difference in the pattern of movement of NER proteins in cultured cells from XP or TTD patients with different XPD defects. In XP cells at late times after UV, the NER proteins persisted at sites of unrepaired DNA damage. In contrast, in TTD cells the NER proteins did not persist. These differences suggest a mechanism that may explain the difference between the increased cancer susceptibility in XP patients and the absence of increased cancer in TTD. There was a similar persistence of NER proteins at sites of DNA damage in cells with defects in the XPC, XPB and DDB2/XPE genes. While skin cancer is the most common cancer occurring in the US, and rates of melanoma, the most dangerous skin cancer are rapidly increasing, there remains controversy as to the role of UV in induction of cutaneous melanomas. Because of their high frequency of melanomas, XP patients are a unique resource to study the pathophysiology of melanoma. We used laser capture micro-dissection to remove melanoma cells from tissue blocks of XP melanomas and sequenced the PTEN tumor suppressor gene. We found a high frequency of UV-type mutations in 59 XP melanomas. These data provide evidence for a direct effect of UV in the development of melanoma. We determined that a unique patient with melanoma, deafness and DNA repair deficiency had a translocation between chromosomes 9 and 22. His cells had a break in the p14arf tumor suppressor gene on chr 9 leading to reduced DNA repair and melanoma. Expression of TBX1, a gene on chr 22 that is important in ear development was reduced in his cells. The translocation produced a chimeric mRNA that served as a dominant negative regulator of p14arf and TBX1. This provides important insights into the causes of melanoma and regulation of inner ear development.

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Kuschal, Christiane; Botta, Elena; Orioli, Donata et al. (2016) GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy. Am J Hum Genet 98:627-42
Kraemer, Kenneth H; DiGiovanna, John J (2015) Forty years of research on xeroderma pigmentosum at the US National Institutes of Health. Photochem Photobiol 91:452-9
Heller, Elizabeth R; Khan, Sikandar G; Kuschal, Christiane et al. (2015) Mutations in the TTDN1 gene are associated with a distinct trichothiodystrophy phenotype. J Invest Dermatol 135:734-41
Kuschal, Christiane; Khan, Sikandar G; Enk, Benedikt et al. (2015) Readthrough of stop codons by use of aminoglycosides in cells from xeroderma pigmentosum group C patients. Exp Dermatol 24:296-7
Tamura, Deborah; DiGiovanna, John J; Khan, Sikandar G et al. (2014) Living with xeroderma pigmentosum: comprehensive photoprotection for highly photosensitive patients. Photodermatol Photoimmunol Photomed 30:146-52
Atkinson, Emily C; Thiara, Diana; Tamura, Deborah et al. (2014) Growth and nutrition in children with trichothiodystrophy. J Pediatr Gastroenterol Nutr 59:458-64
Kraemer, Kenneth H; DiGiovanna, John J (2014) Global contributions to the understanding of DNA repair and skin cancer. J Invest Dermatol 134:E8-17
Kuschal, Christiane; DiGiovanna, John J; Khan, Sikandar G et al. (2013) Repair of UV photolesions in xeroderma pigmentosum group C cells induced by translational readthrough of premature termination codons. Proc Natl Acad Sci U S A 110:19483-8
Viana, Lucas M; Seyyedi, Mohammad; Brewer, Carmen C et al. (2013) Histopathology of the inner ear in patients with xeroderma pigmentosum and neurologic degeneration. Otol Neurotol 34:1230-6
Brooks, Brian P; Thompson, Amy H; Bishop, Rachel J et al. (2013) Ocular manifestations of xeroderma pigmentosum: long-term follow-up highlights the role of DNA repair in protection from sun damage. Ophthalmology 120:1324-36

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