Xeroderma pigmentosum （XP） is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underly...Xeroderma pigmentosum （XP） is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underlying mechanism is unknown, in part due to lack of proper disease models. Here, we generated patientspecific induced pluripotent stem cells （iPSCs） harboring mutations in five different XP genes including XPA, XPB, XPC, XPG, and XPV. These iPSCs were further differentiated to neural cells, and their susceptibility to DNA damage stress was investigated. Mutation of XPA in either neural stem cells （NSCs） or neurons resulted in severe DNA damage repair defects, and these neural cells with mutant XPA were hyper-sensitive to DNA damage-induced apoptosis. Thus, XP-mutant neural cells represent valuable tools to clari the molecular mechanisms of neurological abnormalities in the XP patients.展开更多
In xeroderma pigmentosum, a rare genodermatosis, transmitted as an autosomal recessive disorder, excessive solar damage to the skin develops at an early age. The disease is characterized by cutaneous, ocular, neurolog...In xeroderma pigmentosum, a rare genodermatosis, transmitted as an autosomal recessive disorder, excessive solar damage to the skin develops at an early age. The disease is characterized by cutaneous, ocular, neurological and oral changes. Oral features in the form of early development of Squamous cell carcinoma, usually at the lower lip and tip of the tongue may be seen. The disorder is associated more commonly in populations where marriage of close blood relatives is common. Treatment of the disorder includes avoidance of Ultra violet radiation, topical application of 5 fluorouracil to treat actinic keratoses, and regular evaluation by an optholmologist, dermatologist, and neurologist. Genetic counseling is an important aspect as an increased incidence of consanguineous marriages have been reported with this disorder. Here, we report an interesting case of xeroderma pigmentosum in an 18 year old male patient who presented with characterstic desquamation of gingiva, fissured tongue and geoghraphic tongue.展开更多
Xeroderma pigmentosum is a rare, autosomal recessive disease caused by a defect in DNA repair. Patients with xeroderma pigmentosum often have cutaneous and ocular sun sensitivity, freckle-like skin pigmentation, multi...Xeroderma pigmentosum is a rare, autosomal recessive disease caused by a defect in DNA repair. Patients with xeroderma pigmentosum often have cutaneous and ocular sun sensitivity, freckle-like skin pigmentation, multiple skin and eye cancers, and, in some patients, progressive neurodegeneration. Xeroderma pigmentosum predominantly affects the ultraviolet (UV) exposed ocular surface, resulting in eyelid atrophy and cancers, corneal dryness, exposure keratopathy, and conjunctival tumors. General features included parental consanguinity (40%), familiarity (60%), onset of symptoms in the first 2 years (50%), malignant skin neoplasms (60%), and carcinoma of the tongue (20%). Among the ocular features, 50% of patients presented with photophobia. Lid freckles or atrophic skin lesions were seen in all patients. Lower lid tumours were seen in 30%, chronic conjunctival congestion in 40%, corneal opacification in 40%, squamous cell carcinoma of limbus in 20%, bilateral pterygium in 40%, and visual impairment in 50%. We report the clinical history and ocular pathology of a boy who is having xeroderma pigmentosum with ocular manifestations. The ophthalmic manifestations of xeroderma pigmentosum are discussed and reviewed with respect to this report and other cases in the literature. These cases illustrate the role of DNA repair in protection of the eyes from UV damage and neuron degeneration of the retina.展开更多
目的探讨1个C组着色性干皮病家系XPC （XPC complex subunit, DNA damagerecognition and repair factor）基因的突变情况。方法采用高通量测序和Sanger测序技术对先证者进行突变分析。在确定突变后，对其父母进行致病基因位点确认；用...目的探讨1个C组着色性干皮病家系XPC （XPC complex subunit, DNA damagerecognition and repair factor）基因的突变情况。方法采用高通量测序和Sanger测序技术对先证者进行突变分析。在确定突变后，对其父母进行致病基因位点确认；用逆转录-PCR检测突变对mRNA的影响。结果先证者携带XPC基因c．2098G〉T和c．2034-7_2040del复合杂合突变，其中c．2098G〉T突变导致第700位的氨基酸由Gly变为终止密码子，而c．2034-7_2040del突变导致mRNA缺失了第11外显子的82个核苷酸，使肽链从940个氨基酸截短至679个，两个突变分别遗传自其父母。在100名无亲缘关系的正常对照中未检测到上述突变。结论XPC基因c．2098G〉T和c．2034-7_2040del复合杂合突变可导致XPC基因表达异常，造成XPC功能减弱或丧失，可能是该患者的发病原因。展开更多
基金This work was supported by National Basic Research Program （973 Program） （Nos. 2015CB964800 and 2014CB910503）, the Strategic Priority Research Program of the Chinese Academy of Sciences （XDA01020312）, National High Technology Research and Development Program of China （2015AA020307）, National Natural Science Foundation of China （Grant Nos. 81330008, 31222039, 31201111, 81371342, 81300261, 81300677, 81271266, 81471414, 81422017, and 81401159）, Beijing Natural Science Foundation （7141005 5142016）, Program of Beijing Municipal Science and Technology Commission （Z151100003915072）, Key Research Program of the Chinese Academy of Sciences （KJZDEW-TZ-L05）, the Thousand Young Talents program of China, National Laboratory of Biomacromolecules （012kf02, 2013kf05, 2013kf11, 2014kf02, 2015kfl 0）. J.C.I.B. was supported by UCAM, the G. Harold and Leila Y. Mathers Charitable Foundation, the Leona M. and Harry B. Helmsley Charitable Trust （2012-PG-MED002） and the Moxie Foundation.
文摘Xeroderma pigmentosum （XP） is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underlying mechanism is unknown, in part due to lack of proper disease models. Here, we generated patientspecific induced pluripotent stem cells （iPSCs） harboring mutations in five different XP genes including XPA, XPB, XPC, XPG, and XPV. These iPSCs were further differentiated to neural cells, and their susceptibility to DNA damage stress was investigated. Mutation of XPA in either neural stem cells （NSCs） or neurons resulted in severe DNA damage repair defects, and these neural cells with mutant XPA were hyper-sensitive to DNA damage-induced apoptosis. Thus, XP-mutant neural cells represent valuable tools to clari the molecular mechanisms of neurological abnormalities in the XP patients.
文摘In xeroderma pigmentosum, a rare genodermatosis, transmitted as an autosomal recessive disorder, excessive solar damage to the skin develops at an early age. The disease is characterized by cutaneous, ocular, neurological and oral changes. Oral features in the form of early development of Squamous cell carcinoma, usually at the lower lip and tip of the tongue may be seen. The disorder is associated more commonly in populations where marriage of close blood relatives is common. Treatment of the disorder includes avoidance of Ultra violet radiation, topical application of 5 fluorouracil to treat actinic keratoses, and regular evaluation by an optholmologist, dermatologist, and neurologist. Genetic counseling is an important aspect as an increased incidence of consanguineous marriages have been reported with this disorder. Here, we report an interesting case of xeroderma pigmentosum in an 18 year old male patient who presented with characterstic desquamation of gingiva, fissured tongue and geoghraphic tongue.
文摘Xeroderma pigmentosum is a rare, autosomal recessive disease caused by a defect in DNA repair. Patients with xeroderma pigmentosum often have cutaneous and ocular sun sensitivity, freckle-like skin pigmentation, multiple skin and eye cancers, and, in some patients, progressive neurodegeneration. Xeroderma pigmentosum predominantly affects the ultraviolet (UV) exposed ocular surface, resulting in eyelid atrophy and cancers, corneal dryness, exposure keratopathy, and conjunctival tumors. General features included parental consanguinity (40%), familiarity (60%), onset of symptoms in the first 2 years (50%), malignant skin neoplasms (60%), and carcinoma of the tongue (20%). Among the ocular features, 50% of patients presented with photophobia. Lid freckles or atrophic skin lesions were seen in all patients. Lower lid tumours were seen in 30%, chronic conjunctival congestion in 40%, corneal opacification in 40%, squamous cell carcinoma of limbus in 20%, bilateral pterygium in 40%, and visual impairment in 50%. We report the clinical history and ocular pathology of a boy who is having xeroderma pigmentosum with ocular manifestations. The ophthalmic manifestations of xeroderma pigmentosum are discussed and reviewed with respect to this report and other cases in the literature. These cases illustrate the role of DNA repair in protection of the eyes from UV damage and neuron degeneration of the retina.
文摘目的探讨1个C组着色性干皮病家系XPC （XPC complex subunit, DNA damagerecognition and repair factor）基因的突变情况。方法采用高通量测序和Sanger测序技术对先证者进行突变分析。在确定突变后，对其父母进行致病基因位点确认；用逆转录-PCR检测突变对mRNA的影响。结果先证者携带XPC基因c．2098G〉T和c．2034-7_2040del复合杂合突变，其中c．2098G〉T突变导致第700位的氨基酸由Gly变为终止密码子，而c．2034-7_2040del突变导致mRNA缺失了第11外显子的82个核苷酸，使肽链从940个氨基酸截短至679个，两个突变分别遗传自其父母。在100名无亲缘关系的正常对照中未检测到上述突变。结论XPC基因c．2098G〉T和c．2034-7_2040del复合杂合突变可导致XPC基因表达异常，造成XPC功能减弱或丧失，可能是该患者的发病原因。
