Xeroderma Pigmentosum: A Heterogeneous Disease with Pockets of Homogeneity

Abstract

QUESTIONS 1. Describe the features of the different types of xeroderma pigmentosum. 2. What is a founder effect? 3. What is the proposed hypothesis and rationale for this study? 4. What methods were employed in the study, and what were the results? 5. What were the conclusions and clinical implications? The occurrence of rare genetic diseases at higher than anticipated rates in selected populations may be the result of a common ancestor in such populations. This phenomenon is referred to as the founder effect. One such example is the occurrence of xeroderma pigmentosum (XP) in the population in the five-country region of North Africa called the Maghreb. In this population, XP occurs more commonly than in other parts of the world. XP is the prototypical nucleotide excision repair (NER) disorder. Via a multistep reaction, NER ordinarily eliminates DNA-distorting lesions caused by UV-induced photoproducts. The two branches of NER are global genome repair (GGR) and transcription-coupled repair. GGR searches nontranscribed regions of the genome for strand distortions, whereas transcription-coupled repair removes lesions that block RNA polymerase (Hoeijmakers, 2009). Eight subtypes of XP have been described. Specific mutations in one NER protein have been reported for each of the XPA-XPG subtypes, and these subtypes all have defective NER. The eighth type, the XP variant, has normal NER but aberrant translesional synthesis. All patients with XP display photosensitivity of varying degrees. Other cutaneous features of this disease include abnormal pigmentation and frequent skin cancers (Kraemer et al., 1987). Neurologic, growth, and ocular abnormalities vary among the eight subtypes, termed complementation groups. To better characterize this distinct population of patients with XP, Soufir et al. studied Maghrebi patients with XP. Through genetic and molecular analysis of a large cohort of 86 patients, a common XPC mutation was identified. Mathematical modeling was employed to determine the likelihood of a common ancestor. Assuming a 20to 30-year generation time, the original mutation was calculated to have occurred 1,250 years ago; on the basis of these results, a founder effect was proposed. Through the following questions, we examine this paper, as well as the mutations that underlie xeroderma pigmentosum, in greater detail. For brief answers, please refer to the supplementary information online