三个先天性掌跖角化病家系致病基因的染色体定位

目的定位3个先天性掌跖角化病家系的致病基因在染色体上的区间。方法选择位于17q12～q21和12q11～q13内及其附近的微卫星标记D17S1868、D17S787、D17S1857、D17S798、D17S944、D17S949和D12S85、D12S368、D12S83、D12S345对3个掌跖角化病家系进行基因组扫描与连锁分析。结果在17号染色体的2对微卫星标记D17S1868和D17S787上分别得到了总Lod值高达6.59(θ=0.1)和5.96(θ=0.1),每个家系各自的Lod值也在2(θ=0/0.1)以上,提示这3个家系的致病基因与位于该区间的候选基因KRT9呈紧密连锁。结论这3个家系的致病基因被定位于17q12～q21内。     

一个表皮松解性掌跖角化症家系致病基因突变的鉴定

目的本研究旨在鉴定1个广西表皮松解性掌跖角化症(EPPK)家系的KRT9基因致病突变位点。方法收集EPPK家系中8个患者和2个健康成员的血液样本并提取基因组DNA,通过全外显子组测序(WES)分析和筛选潜在突变位点,结合聚合酶链反应(PCR)和Sanger测序对候选突变位点进行验证。结果该家系所有EPPK患者的KRT9基因1号外显子发生杂合错义突变(c.470T>G),导致157位氨基酸由蛋氨酸变成精氨酸(p.M157R),而2个健康成员未发现该位点突变。结论 KRT9基因杂合错义突变c.470T>G是EPPK家系的致病原因,这一发现将有助于该家系成员的遗传咨询、产前诊断和疾病防治。     

一个弥漫性表皮松解性掌跖角化病家系角蛋白9基因R162W突变

目的 研究1个弥漫性表皮松解性掌跖角化病(epidermolytic plamoplantar keratoderma,EPPK)家系中的基因突变情况.方法 收集1个弥漫性表皮松解性掌跖角化病家系的外周血标本,采取聚合酶链反应结合DNA直接测序的方法,检测了该家系中4例患者及3名表型正常者和100名无亲缘关系健康个体的KRT9基因突变情况.结果 该家系中患者存在KR79基因上第484位C突变成T,使得KRTY基因的第1外显子162位密码子由CGG突变成TGG,导致正常精氨酸被色氨酸所取代,而该家系的正常人对照及无关健康个体不存在此突变.结论 EPPK家系中患者KRT9基因存在错义突变(484C→T),这可能是导致EPPK发病的分子机制之一.     

表皮松解性掌跖角化症KRT9基因突变致病机制的研究进展

表皮松解性掌跖角化症(EPPK)是一种较为常见的常染色体显性皮肤遗传病,目前尚无有效的治疗方法。本文总结了引起EPPK角蛋白异常的热点突变基因KRT9及其突变位点,KRT9作为可靠生物学标记已经成功应用于临床产前诊断,阐述角蛋白表达及其调控发病机制的突变Krt9基因敲入小鼠模型,以及靶向特异性sh RNA介导治疗EPPK等研究进展。     

一个表皮松解性掌跖角化病家系的角蛋白9基因突变研究

目的 确定一个中国汉族表皮松解性掌跖角化症(epidermolytic palmoplantar keratoderma,EPPK)家系角蛋白9基因(keration 9,KRT9)的突变情况,并分析基因型与表型的对应关系.方法 收集该家系12例患者、13名健康者和100名无亲缘关系的正常人的外周血,提取基因组DNA.采用PCR扩增KRT9基因的第1和第6外显子,对PCR产物进行双向测序以检测基因突变.结果 在所有患者中均检测到KRT9基因第1外显子中的杂合型488G→A突变,导致第163位的精氨酸被谷氨酰胺取代(R163Q).在家系中13名正常人和家系外100名正常人未检测到同样的突变.结论 KRT9基因的错义突变488G→A是该家系发生表皮松解性掌跖角化症的主要原因.     

表皮松解性掌跖角化症一家系KRT9基因突变研究

目的研究表皮松解性掌跖角化症一家系角蛋白9(keratin 9,KRT9)基因突变情况。方法用聚合酶链反应技术扩增家系成员及家系外5O名正常人KRT9基因外显子1,DNA序列分析寻找突变位点。结果家系中患者KRT9基因外显子1第488位碱基C→T,导致162位的精氨酸被谷氨酸取代(R162Q),家系内正常成员及家系外5O名正常人均不存在此突变。结论 KRT9基因外显子1第488位密码子发生C→T突变导致该家系患者发生表皮松解性掌跖角化症。     

一个表皮松解性掌跖角化病家系的KRT9基因突变分析

目的明确一个伴随有类似关节指垫样病损和指甲病变的表皮松解性掌跖角化病的中国家系中角蛋白9(keratin9,KRT9)基因突变情况。方法用聚合酶链反应技术扩增家系成员及家系外50名正常人KRT9基因的编码区及外显子与内含子交界处,DNA序列分析寻找突变位点,然后经限制性内切酶Dde分析验证。结果患者KRT9基因第1外显子第160位密码子发生AAT→AGT的突变(N160S),而家系正常成员及家系外50个正常人中均不存在此突变。结论KRT9基因的第1外显子第160位密码子发生AAT→AGT突变(N160S)导致该家系患者发生表皮松解性掌跖角化病。     

5个表皮松解性掌跖角化症家系的KRT9基因突变谱分析和产前DNA诊断

目的绘制5个表皮松解性掌跖角化症(EPPK)家系的致病突变谱。应其中3个家系的要求,实施相关的产前DNA诊断。方法分别抽取5个家系相关成员的抗凝外周血,纯化基因组DNA。PCR扩增EPPK的主要致病基因角蛋白9(KRT9)的编码氨基酸的全部7个外显子(第1~7外显子)及其相邻DNA区域的序列,Sanger测序鉴定基因突变。用AS-PCR法验证所发现的KRT9基因突变。抽取3个家系的相关孕妇的羊水,纯化胎儿基因组DNA,PCR、Sanger测序和AS-PCR法确定胎儿的KRT9基因型。结果 2个EPPK家系的致病基因KRT9突变为最常见的突变:位于第1外显子的c.487CT(p.Arg163Trp)杂合性错义突变;其余3个家系的杂合性错义突变分别为:c.482AG(p.Asn161Ser)、c.488GA(p.Arg163Gln)和c.566AG(p.Tyr167Cys)。遗憾的是,3个家系的产前DNA诊断均显示胎儿存在对应的KRT9基因突变,表明为患病。结论对于临床上疑似为EPPK的家系,可快速筛查KRT9基因突变,辅助临床精准诊断本病。在首先确定了家系的基因突变谱之后,可行羊膜穿刺术或PGD,以预防EPPK患儿的出生,实现优生优育。     

家族性高甘油三酯血症家系的候选基因位点连锁分析

目的 对一个家族性高甘油三酯血症(familial hypertriglyceridemia,FHTG)家系进行遗传连锁定位及基因突变分析.方法 32名家系成员,其中12例为高甘油三酯血症(hypertriglyceridemia)患者.应用短串联重复(short tandem repeat,STR)片段微卫星标记物对其中的22名成员进行了16个与脂代谢有关的候选基因和(或)位点的遗传连锁分析和单倍型分析,并对其中的两个候选基因APOA2和USF1直接测序以筛查突变.结果 APOA5、LIPI、RP1、APOC2、ABC1,LMF1、APOA1-APOC3-APOA4、LPL,APOB、CETP、LCAT,LDLR,APOE等候选基因位点与该家系表型不连锁,Lod值均小于-1.0(θ=0).遗传连锁分析提示位于1q23.3-24.2染色体区域,疾病表型在D1S104至D1S196之间(遗传间距为5.87 cM)存在连锁,其中D1S194两点间最大Lod值为2.44(θ=0).对APOA2和USF1基因的序列分析未发现致病突变.结论 排除了上述候选基因为本家系的致病基因;提示在1q23.3-1q24.2染色体区域可能存在一个新的与FHTG相关的基因.     

先天性视网膜脉络膜缺损一家系基因连锁定位分析

目的 对一个连续3代常染色体显性遗传性先天性视网膜脉络膜缺损(autosomal dominant congenital retinaochoroidal coloboma)家系进行致病基因的连锁定位分析.方法 对家系所有成员进行详细的临床检查,排除其他系统疾患.提取家系成员外周血DNA,选取位于全部染色体上的398对微卫星标记物,进行全基因组扫描.经ABI3130型遗传分析仪,Genescan收集数据,Genotyper进行基因分型,Linkage软件计算两点Lod值.结果 在2号染色体长臂上的微卫星标记物D2S2382取得最大的Lod值,其Lod值为3.01.进一步在D2S2382附近选择微卫星标记物,进行连锁分析,发现微卫星标记物D2S2382-D2S301-D2S2244-D2S163与家系中所有患者疾病表型共分离.结论 将一个常染色体显性遗传性先天性视网膜脉络膜缺损家系的致病基因定位于2q34-2q35之间的3.80 cM范围内.     

一个遗传性乳光牙本质家系致病基因的初步定位

目的：研究遗传性乳光牙本质家系致病基因是否与染色体４ｑ２１连锁。方法：提取在天津塘沽地区发现的一个遗传性乳光牙本质家系成员的外周血ＤＮＡ,选择染色体４ｑ２１上的４仆短串联重复序列多态性标记（ｓｈｏｒｔ ｔａｎｄｅｍ ｒｅｐｅａｔ ｐｏｌｙｍｏｒｐｈｉｓｍ,ＳＴＲＰ）：ＧＡＴＡ６２Ａ１１、ＤＳＰ（Ｐ）、ＳＰＰ１的Ｄ４Ｓ１５６３做荧光标记ＰＣＲ、等位片段分析,用Ｌｏｄ连锁分析法分析该家系致病基因位点与上述４个ＳＴＲ的连锁关系。结果：分别得到１３个家庭成员上述４个位点的基因型和单体型。ＭＬＩＮＫ软件分析显示：ＧＡＴＡ６２Ａ１１、ＫＳＰ（Ｐ）与致病基因位点连锁的最大Ｌｏｄ值分别为１．６３（θ＝０）。结论：遗传性乳光牙本质家系的致病基因初步定位在４号染色体上。     

Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21

Familial frontotemporal dementia (FTD) is a complex disorder with lack of distinctive histopathological markers found in other types of dementia. Most of the linkage reports from FTD families map the disease loci to chromosome 17q21-22. However, FTD is genetically heterogeneous, as linkage also has been reported to chromosome 3. In the present study, we investigated the genetics of a Swedish family with an early-onset type of rapidly progressive FTD, associated with muscular rigidity and akinetic movements. Neuropathological features such as severe frontal lobe degeneration, spongy changes, and gliosis were present in affected family members. We here report probable linkage to chromosome 17q12-21 with a maximum two-point lod score of 2.76 at θ = 0 for marker D17S806, and a peak multipoint lod score of 2.86 for the same marker. Linkage to chromosome 3 was excluded, as two-point lod scores of −2.79, and −2.27 at θ = 0.01 for markers D3S1603 and D3S1552, respectively, were obtained. Sequencing of the translated exons of a strong candidate gene in the linked region of chromosome 17, the tau gene, failed to identify any mutations segregating with the disease. Am. J. Med. Genet. 74:380–385, 1997. © 1997 Wiley-Liss, Inc.     

Fine mapping study in Scandinavian families suggests association between coeliac disease and haplotypes in chromosome region 5q32

The previous genome-wide scan in Scandinavian families supported earlier evidence for linkage of a region on chromosome 5 (5q31-33) to coeliac disease. This study deals with further genetic mapping of an 18 cM region, spanning from marker GAh18A (131.87 Mb) to D5S640 (149.96 Mb). Linkage and association analyses were performed in a two-step approach. First, seven microsatellites were added. Strong evidence for linkage was obtained with a Zlr score of 3.96, P(nc) = 4 x 10(-5) at marker D5S436. The strongest association was with a haplotype consisting of the markers D5S2033 and D5S2490 (P(nc) < 0.001). In the second step, we added 17 microsatellites and 69 single nucleotide polymorphisms (SNPs) to the analysis. These markers were located close to or within candidate genes across the region of approximately 7 Mb beneath the linkage peak marked by D5S2017 and D5S812. A substantial increase of the linkage signal with a maximum Zlr score of 4.6 at marker rs1972644 (P(nc) = 2 x 10(-6)) was obtained and several SNPs showed association. Seven SNPs that individually showed the strongest association were genotyped in a second independent family sample set (225 trios). In the trio family sample as well as in the multiplex family sample, the strongest association was found with SNPs within the region flanked by the associated microsatellites D5S2033 and D5S2490 at 5q32.     

Linkage refinement localises Sorsby fundus dystrophy between markers D22S275 and D22S278.

Sorsby fundus dystrophy is an autosomal dominant disorder which both clinically and histopathologically bears striking similarities to age related macular degeneration, one of the leading causes of blindness in the developed world. Recent studies have suggested a genetic localisation of the disease to chromosome 22q in a large genetic interval of approximately 25 cM. Independent genetic linkage analysis in a six generation British pedigree confirms linkage to the chromosome 22q region. A maximum two point lod score of 7.09 with no recombination was obtained with marker D22S280. Haplotype data positioned the disease between loci D22S275 and D22S278, thus significantly reducing the region on chromosome 22q where the gene is located.     

Genetic linkage study for bipolar disorders on chromosomes 17 and 18 in families with a high expression of mental illness from the Balearic Islands

Genetically, bipolar disorder is a complex genetic illness, in which both genes and environmental factors play an important role in pathogenesis. Linkage studies have reported suggestive evidence for genomic regions, especially on chromosome 18, but in most cases they have been inconclusive. A total of 12 pedigrees, from the islands of Majorca and Minorca (Balearic Archipelago), with a high expression of mental illness, have been studied. A scan of 29 polymorphic short tandem repeat markers was performed, spanning chromosomes 17 and 18 for bipolar and other affective disorder susceptibility loci. Narrow (only bipolar I disorder) and broad (bipolar plus other affective disorders) diagnosis criteria were employed. The loci D18S63, D18S452, D18S53, D18S61, D18S1161 and D17S831 showed LOD score values of less than -2. Thus, the positive linkage found by other authors on the regions 18p11.2 and 18p11.3 has not been reproduced in the families studied. The data obtained in chromosome 17 suggested two possible regions that could contain a bipolar disorder susceptibility gene: 17q11 (D17S1857, D17S798) and especially 17q24-qter (D17S949, D17S928). The maximum significant linkage was to D17S949 (17q24), following a recessive mode of inheritance. We have also found a positive LOD score value for D18S478 marker located in the region 18q12.     

先天性视网膜脉络膜缺损一家系基因连锁定位分析

目的 对一个连续3代常染色体显性遗传性先天性视网膜脉络膜缺损(autosomal dominant congenital retinaochoroidal coloboma)家系进行致病基因的连锁定位分析.方法 对家系所有成员进行详细的临床检查,排除其他系统疾患.提取家系成员外周血DNA,选取位于全部染色体上的398对微卫星标记物,进行全基因组扫描.经ABI3130型遗传分析仪,Genescan收集数据,Genotyper进行基因分型,Linkage软件计算两点Lod值.结果 在2号染色体长臂上的微卫星标记物D2S2382取得最大的Lod值,其Lod值为3.01.进一步在D2S2382附近选择微卫星标记物,进行连锁分析,发现微卫星标记物D2S2382-D2S301-D2S2244-D2S163与家系中所有患者疾病表型共分离.结论 将一个常染色体显性遗传性先天性视网膜脉络膜缺损家系的致病基因定位于2q34-2q35之间的3.80 cM范围内.     

先天性视网膜脉络膜缺损一家系基因连锁定位分析

目的 对一个连续3代常染色体显性遗传性先天性视网膜脉络膜缺损(autosomal dominant congenital retinaochoroidal coloboma)家系进行致病基因的连锁定位分析.方法 对家系所有成员进行详细的临床检查,排除其他系统疾患.提取家系成员外周血DNA,选取位于全部染色体上的398对微卫星标记物,进行全基因组扫描.经ABI3130型遗传分析仪,Genescan收集数据,Genotyper进行基因分型,Linkage软件计算两点Lod值.结果 在2号染色体长臂上的微卫星标记物D2S2382取得最大的Lod值,其Lod值为3.01.进一步在D2S2382附近选择微卫星标记物,进行连锁分析,发现微卫星标记物D2S2382-D2S301-D2S2244-D2S163与家系中所有患者疾病表型共分离.结论 将一个常染色体显性遗传性先天性视网膜脉络膜缺损家系的致病基因定位于2q34-2q35之间的3.80 cM范围内.     

先天性视网膜脉络膜缺损一家系基因连锁定位分析

目的 对一个连续3代常染色体显性遗传性先天性视网膜脉络膜缺损(autosomal dominant congenital retinaochoroidal coloboma)家系进行致病基因的连锁定位分析.方法 对家系所有成员进行详细的临床检查,排除其他系统疾患.提取家系成员外周血DNA,选取位于全部染色体上的398对微卫星标记物,进行全基因组扫描.经ABI3130型遗传分析仪,Genescan收集数据,Genotyper进行基因分型,Linkage软件计算两点Lod值.结果 在2号染色体长臂上的微卫星标记物D2S2382取得最大的Lod值,其Lod值为3.01.进一步在D2S2382附近选择微卫星标记物,进行连锁分析,发现微卫星标记物D2S2382-D2S301-D2S2244-D2S163与家系中所有患者疾病表型共分离.结论 将一个常染色体显性遗传性先天性视网膜脉络膜缺损家系的致病基因定位于2q34-2q35之间的3.80 cM范围内.