AJHG：基因拷贝数变异造成多毛症

CGHT是一种极其罕见但遗传性很强的疾病。科学家还没有确定到底有多少人患有这种疾病，但是在中国的10多亿人口中至少有30例。患病的男女全身和面部长有特黑的毛发，有些患病者还长有宽扁的鼻子、大大的耳朵、大大的嘴巴和厚厚的嘴唇，偶尔还长有大脑袋和大下巴。北京协和医学院的遗传学家张学希望能够发现CGHT的遗传基础，于是他开始在全国搜寻这种病例。几年后，研究小组通过医学文献、互联网甚至是电视节目，搜寻到3个患有此病的家庭（包括16名患病成员）愿意参与该研究。研究人员扫描了这些患者的DNA，并将其与19个未患病的家庭成员进行对比。研究小组将搜寻范围缩小到17号染色体的一小段上，然后寻找一种叫作“拷贝数变异”的基因突变现象。在“拷贝数变异”现象中，大块大块的DNA存在重复或缺失。研究人员在近日出版的《美国人类遗传学杂志》上报道，所有的CGHT患者都存在拷贝数变异现象，在相同的4个基因里都存在DNA缺失，而未患CGHT的家庭成员不存在这种基因突变。张学由此推测，基因突变改变了此处染色体结构，影响了附近基因的产生――附近的一种基因SOX9跟毛发的生长有关。据了解，没有这种基因的老鼠毛发会受损，即患上“秃头症”。张学称，如果CGHT患者的基因突变使17号染色体区域发生改变，就会导致毛囊干细胞中的SOX9蛋白产生过剩，引起过多的毛发生长。“但是所有这一切都纯粹是推测”，张学表示。以色列海法市拉帕波特研究所的毛发疾病专家伊莱・斯普雷彻认为,也许张学清楚地了解某些情况。他指出，另外一种毛发增生的情况被称为“阿姆布拉斯综合征（Ambrassyndrome）”，这种情况跟染色体的重新排列相关，因此有理由相信CGHT的致病原理相同。“该研究向治愈这种疑难疾病迈出了重要的第一步”，斯普雷彻说。（生物谷Bioon.com）生物谷推荐原始出处：TheAmericanJournalofHumanGenetics,Volume84,Issue6,807-813,21May2009Copy-NumberMutationsonChromosome17q24.2-q24.3inCongenitalGeneralizedHypertrichosisTerminaliswithorwithoutGingivalHyperplasiaMiaoSun1,11,NingLi2,11,WuDong3,ZugenChen4,QingLiu1,YimingXu1,GuangHe5,YongyongShi5,XinLi6,JiajieHao7,YangLuo2,DandanShang1,DanLv1,FenMa1,DaiZhang1,RuiHua1,ChaoxiaLu1,YaranWen1,LihuaCao2,AlanD.Irvine8,W.H.IrwinMcLean9,QiDong3,Ming-RongWang7,JunYu6,LinHe5,10,WilsonH.Y.Lo1andXueZhang1,2,,1McKusick-ZhangCenterforGeneticMedicineandStateKeyLaboratoryofMedicalMolecularBiology,InstituteofBasicMedicalSciences,ChineseAcademyofMedicalSciences&PekingUnionMedicalCollege,Beijing100005,China2TheResearchCenterforMedicalGenomics,ChinaMedicalUniversity,Shenyang110001,China3ThePeople'sHospitalofLiaoningProvince,Shenyang110016,China4DepartmentofHumanGenetics,DavidGeffenSchoolofMedicine,UniversityofCaliforniaatLosAngeles,LosAngeles,CA90095,USA5Bio-XCenter,ShanghaiJiaoTongUniversity,Shanghai200030,China6BeijingInstituteofGenomics,ChineseAcademyofSciences,Beijing100029,China7StateKeyLaboratoryofMolecularOncology,CancerInstitute（Hospital）,ChineseAcademyofMedicalSciences&PekingUnionMedicalCollege,Beijing100021,China8DepartmentofPediatricDermatology,OurLady'sChildren'sHospital,Dublin12,Ireland9EpithelialGeneticsGroup,DivisionofMolecularMedicine,CollegesofLifeSciencesandMedicine,Dentistry&Nursing,UniversityofDundee,DundeeDD15EH,Scotland,UK10InstitutesofBiomedicalSciences,FudanUniversity,Shanghai200032,ChinaCongenitalgeneralizedhypertrichosisterminalis（CGHT）isarareconditioncharacterizedbyuniversalexcessivegrowthofpigmentedterminalhairsandoftenaccompaniedwithgingivalhyperplasia.Inthepresentstudy,wedescribethreeHanChinesefamilieswithautosomal-dominantCGHTandasporadiccasewithextremeCGHTandgingivalhyperplasia.Wefirstdidagenome-widelinkagescaninalargefour-generationfamily.OurparametricmultipointlinkageanalysisrevealedageneticlocusforCGHTonchromosome17q24.2-q24.3.Furthertwo-pointlinkageandhaplotypingwithmicrosatellitemarkersfromthesamechromosomeregionconfirmedthegeneticmappingandshowedinallthefamiliesamicrodeletionwithinthecriticalregionthatwaspresentinallaffectedindividualsbutnotinunaffectedfamilymembers.Wethencarriedoutcopy-numberanalysiswiththeAffymetrixGenome-WideHumanSNPArray6.0anddetectedgenomicmicrodeletionsofdifferentsizesandwithdifferentbreakpointsinthethreefamilies.Wevalidatedthesemicrodeletionsbyreal-timequantitativePCRandconfirmedtheirperfectcosegregationwiththediseasephenotypeinthethreefamilies.Inthesporadiccase,however,wefoundadenovomicroduplication.Two-colorinterphaseFISHanalysisdemonstratedthattheduplicationwasinverted.Thesecopy-numbervariations（CNVs）sharedacommongenomicregioninwhichCNVisnotreportedinthepublicdatabaseandwasnotdetectedinour434unrelatedHanChinesenormalcontrols.Thus,pathogeniccopy-numbermutationson17q24.2-q24.3areresponsibleforCGHTwithorwithoutgingivalhyperplasia.OurworkidentifiesCGHTasagenomicdisorder.

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