中国首例ADULT综合征家系的p63基因突变研究

发布时间：2018-06-29 21:30

本文选题：ADULT综合征 + p63基因　；参考：《广州医学院》2010年硕士论文

【摘要】：研究背景 ADULT综合征(acro-dermato-ungual-lacrimal-tooth syndrome,OMIM 103285)是一种典型的外胚层发育异常综合征。现在认为ADULT综合征的发生与p63基因错义突变有关。 P63基因在胚胎发育(特别是在四肢和其他外胚层衍生器官的发育)中的重要作用,它在皮肤的基底细胞、子宫颈、舌、食道、乳腺、前列腺、泌尿道上皮中高度表达。动物实验证明p63基因缺陷的小鼠可以发生外胚层顶脊发育缺陷,这种小鼠四肢截短,毛囊、牙齿、泪腺或唾液腺、皮肤、前列腺、乳腺和尿道上皮等结构缺如。目前全球仅有数个已报道的ADULT综合征家系,发病率低,但由于其造成严重畸形所以危害性大,临床表现及基因具体突变位点也存在多样性,增加了诊断的难度。ADULT综合征的遗传学特点仍未十分清楚,对该疾病的基因学进一步研究有助于该病诊断、预防和治疗。研究目的明确中国首例ADULT综合征家系的基因突变位点,探讨p63基因的突变与ADULT综合征发病的关系,为临床基因诊断和治疗提供参考。研究对象和方法该研究对中国首例ADULT综合征患者及其家系成员的临床特点进行分析,采集患者及其家系17名成员的血液样本,提取DNA,以p63基因作为目标基因,采用PCR扩增p63基因全部编码外显子,对扩增产物测序并进行分析。针对检出的突变位点,设立正常对照组(56例)加以验证。研究结果患者的893位点发生杂合性突变(GA),导致编码氨基酸的密码子由CGA变为CAA(由精氨酸变为谷氨酰胺,即R298Q)。而且,一个单核苷酸多态性(SNP)rs16864880在患者及部分父系成员(包括其父亲)p63基因第8外显子下游的旁侧区出现C/G基因型,而在母系成员未发现该基因型,发生率显著少于父系(6/10 vs 0/6,P=0.034)。结论中国首例ADULT综合征患者的p63基因第8外显子发生了R298Q突变,p63基因的突变与ADULT综合征的发病相关,而且该病例的发生与其父系家族有更多的遗传学相关性。
[Abstract]:Background: acro-dermato-ungual-lacrimal-tooth syndrome (acro-dermato-ungual-lacrimal-tooth syndrome OMIM 103285) is a typical ectodermal dysplasia syndrome. It is believed that the pathogenesis of ADULT syndrome is related to the missense mutation of p63 gene. P63 gene plays an important role in embryonic development, especially in the development of limbs and other ectodermal organs, in the basal cells of the skin, in the cervix. Tongue, esophagus, mammary gland, prostate, and urothral epithelium are highly expressed. Animal experiments showed that p63 gene deficient mice could develop ectodermal parietal ridge defects, such as truncated limbs, hair follicles, teeth, lacrimal glands or salivary glands, skin, prostate, mammary gland and urethral epithelium. At present, there are only a few reported families with ADULT syndrome in the world. The incidence is low, but it is harmful because of its serious malformation, and there is also diversity in clinical manifestations and gene specific mutation sites. The genetic characteristics of ADULT syndrome are not very clear. Further study on the genetics of this disease is helpful to diagnosis, prevention and treatment of the disease. Objective to identify the gene mutation site of the first Chinese family with ADULT syndrome and to explore the relationship between the mutation of p63 gene and the pathogenesis of ADULT syndrome so as to provide reference for clinical gene diagnosis and treatment. Subjects and methods the clinical characteristics of the first Chinese patients with ADULT syndrome and their family members were analyzed. Blood samples from 17 members of the patients and their families were collected, DNA was extracted and p63 gene was used as the target gene. All the exons encoding p63 gene were amplified by PCR, and the amplified products were sequenced and analyzed. A normal control group (56 cases) was established to verify the mutation sites detected. The results showed that heterozygosity mutation (GA) occurred at locus 893, which changed the codon encoding amino acid from CGA to CAA (from arginine to glutamine, that is, R298Q). Moreover, a single nucleotide polymorphism (SNPs) rs16864880 had a C / R genotype in the downstream region of exon 8 of p63 gene in patients and some paternal members (including their father), but it was not found in matrilineal members, and the incidence was significantly lower than that in paternal lines (6 / 10 vs 0 / 0 / 6 / P0. 034). Conclusion the mutation of R298Q mutation in exon 8 of p63 gene in the first Chinese patients with ADULT syndrome is associated with the pathogenesis of ADULT syndrome, and the occurrence of this case has more genetic correlation with the paternal family.
【学位授予单位】：广州医学院
【学位级别】：硕士
【学位授予年份】：2010
【分类号】：R758.5

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