Kraemer K H, Patronas N J, Schiffmann R, Brooks B P, Tamura D, DiGiovanna J J
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. 2007 Apr 14;145(4):1388-96. doi: 10.1016/j.neuroscience.2006.12.020. Epub 2007 Feb 1.
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.
患有罕见遗传性疾病色素性干皮病（XP）、毛发硫营养不良症（TTD）和科凯恩综合征（CS）的患者存在DNA核苷酸切除修复（NER）缺陷。NER途径涉及至少28个基因。三个NER基因也是基础转录因子TFIIH的一部分。11个NER基因的突变与至少具有八种重叠表型的临床疾病相关。这些患者的临床特征有一些相似之处，但也有明显差异。NER参与抵御阳光诱导的DNA损伤。虽然XP患者患皮肤癌的易感性增加了1000倍，但TTD和CS患者患皮肤癌的风险正常。一些参与NER的基因也影响体细胞生长和发育。一些患者身材矮小且性发育不成熟。TTD患者有硫缺乏的脆发。进行性感觉神经性耳聋是XP和CS的早期特征。许多这些临床疾病与发育迟缓及进行性神经退行性变有关。XP的主要神经病理学是原发性神经元变性。相比之下，CS和TTD患者大脑的髓鞘形成减少。这些复杂的神经异常与阳光照射无关，可能是由发育缺陷以及氧化代谢或其他内源性过程诱导的神经元细胞DNA损伤修复缺陷引起的。
