本文選題：掌跖角質(zhì)化　切入點(diǎn)：表皮松解掌跖角質(zhì)化　出處：《暨南大學(xué)》2010年碩士論文

【摘要】： 研究背景 表皮松解性掌跖角化癥(epidermolytic palmoplantar keratoderma, EPPK)為常染色體顯性遺傳性皮膚病,其臨床特征表現(xiàn)為掌跖角質(zhì)層過度增厚。組織學(xué)特點(diǎn)為角質(zhì)形成細(xì)胞空泡變性,大量裂解。該病有并發(fā)乳腺癌或卵巢癌的風(fēng)險(xiǎn)。EPPK主要由位于17q12-q21上的KRT9基因突變所致。KRT9基因的缺陷破壞了中間纖維的形成,導(dǎo)致細(xì)胞的結(jié)構(gòu)及功能發(fā)生改變。在已經(jīng)報(bào)道的EPPK家系中,KRT9基因的第1外顯子是突變發(fā)生的熱區(qū)。 目的 通過對(duì)一EPPK家系病例進(jìn)行分子遺傳學(xué)研究,探討EPPK的發(fā)病機(jī)制。通過檢索人類中間纖維突變數(shù)據(jù)庫(kù),分析國(guó)內(nèi)外報(bào)道的EPPK家系,進(jìn)一步探討EPPK的分子遺傳學(xué)機(jī)制及基因型與表型的關(guān)系。 材料與方法 收集1例來(lái)自廣東梅州的EPPK家系,其中患者11人,共累及5代人。選擇20名無(wú)親緣關(guān)系的正常人作為對(duì)照。應(yīng)用聚合酶鏈?zhǔn)椒磻?yīng)(PCR)及DNA測(cè)序的方法對(duì)該家系中7名患者和4名正常成員的KRT9基因進(jìn)行檢測(cè)。 結(jié)果 1.表皮松解掌跖角化癥存在遺傳異質(zhì)性,即使同一個(gè)家系,家系成員掌跖角質(zhì)化的程度卻有所不同, 2.應(yīng)用PCR及DNA測(cè)序分析方法,確診到中國(guó)人群中的7例掌跖角化癥。該家系中7例患者的KRT9基因第1外顯子中的第156位密碼子發(fā)生ATG→ACG的突變,導(dǎo)致甲硫氨酸(Met)被蘇氨酸(Thr)取代。 3.在非編碼區(qū)檢測(cè)到KRT9基因-99位點(diǎn)存在多態(tài)性(G／A)。 4.由于報(bào)道的病例數(shù)不多,尚不能明確表型與基因型的關(guān)系。 結(jié)論 1.本研究中的7名家系患者均在基因水平上診斷為EPPK患者,主要病因?yàn)椋篕RT9基因第1外顯子的第156位密碼子發(fā)生錯(cuò)義突變,導(dǎo)致甲硫氨酸被蘇氨酸取代。 2.本研究再次證實(shí)中國(guó)人群KRT9基因突變與其他已研究的家系相似,突變位點(diǎn)位于熱區(qū)。 3.推測(cè)KRT9突變導(dǎo)致角蛋白二級(jí)結(jié)構(gòu)的改變：錯(cuò)義突變雖然沒有改變編碼肽鏈的長(zhǎng)度,卻改變氨基酸的理化性質(zhì),導(dǎo)致螺旋構(gòu)象的高度破壞,角蛋白亞單位構(gòu)建異常,最終導(dǎo)致EPPK的臨床表現(xiàn)。 4.可優(yōu)先對(duì)熱區(qū)exon1進(jìn)行測(cè)序來(lái)提高工作效率。如果根據(jù)臨床表型診斷和病理切片初步診斷為EPPK,但對(duì)KRT9的1～7外顯子測(cè)序又未檢出突變,為避免漏診,需要考慮少數(shù)病例中KRT1、KRT10和KRT16突變也可以導(dǎo)致EEPK。
[Abstract]:Research background. Epidermolytic palmoplantar keratoderma (EPPKK) is an autosomal dominant hereditary dermatosis, which is characterized by excessive thickening of palmar metatarsal keratinocytes and histopathological features of vacuolar degeneration of keratinocytes. Mass cleavage. The disease has a risk of developing breast or ovarian cancer. EPPK is mainly caused by a defect in the .KRT9 gene in the KRT9 gene located on 17q12-q21, which destroys the formation of intermediate fibers. The first exon of KRT9 gene is the hot region of mutation in EPPK pedigree. Purpose. By studying the molecular genetics of a EPPK family case, the pathogenesis of EPPK was studied, and the EPPK pedigree reported at home and abroad was analyzed by searching the human intermediate fiber mutation database. To further explore the molecular genetic mechanism of EPPK and the relationship between genotype and phenotype. Materials and methods. A case of EPPK family from Meizhou, Guangdong Province was collected. The KRT9 gene of 7 patients and 4 normal members were detected by polymerase chain reaction (PCR) and DNA sequencing. Results. 1. There is genetic heterogeneity in epidermolysis palmoplantar keratosis. Even in the same family, the degree of palmoplantar keratosis in family members is different. 2. Using PCR and DNA sequencing analysis, 7 cases of palmoplantar keratosis were diagnosed in Chinese population. ATG was found in codon 1 of KRT9 gene in 7 patients in this pedigree. 鈫扵he mutation of ACG causes methionine to be replaced by threonine. 3. KRT9 gene-99 locus was found to be polymorphic in non-coding region. 4. Due to the small number of reported cases, the relationship between phenotype and genotype is not clear. Conclusion. 1. In this study, 7 families were all diagnosed as EPPK patients at the gene level. The main cause was a missense mutation at codon 156 of the first exon of the gene, which led to the replacement of methionine with threonine. 2. This study confirmed that the mutation of KRT9 gene in Chinese population was similar to that in other families, and the mutation locus was located in the hot region. 3. It is speculated that KRT9 mutation leads to the change of the secondary structure of keratin: although the missense mutation does not change the length of the encoded peptide chain, it changes the physicochemical properties of amino acids, resulting in the high destruction of helical conformation, and the abnormal construction of keratin subunits. Finally, the clinical manifestation of EPPK is caused. 4. The hot region exon1 sequencing can be given priority to improve the working efficiency. If EPPKs are initially diagnosed according to clinical phenotype diagnosis and pathological section, but no mutation is detected in KRT9 exon 1 / 7 sequencing, in order to avoid misdiagnosis, It is necessary to consider that KRT1 KRT10 and KRT16 mutations may also lead to EEPK in a few cases.
【學(xué)位授予單位】：暨南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2010
【分類號(hào)】：R758.5

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