一个中国汉族遗传性出血性毛细血管扩张症家系致病基因的定位研究

目的定位一个中国汉族遗传性出血性毛细血管扩张症家系的致病基因。方法选择基因ALK-1及endoglin作为该HHT家系致病基因的候选基因，在候选基因染色体区域进行定位。结果连锁分析结果发现ALK-1染色体区域微卫星遗传标记D12s1586LODZMAX为1．82，D12s1677LODZMAX为1．74，D12s1635LODZMAX为1．65，D12s368 LODZMAX为1．87，支持连锁。构建单体型发现家系内所有患者在ALK-1染色体区域都连锁，无交换重组现象。而endoglin染色体区域微卫星遗传标记连锁分析结果不支持连锁。结论这个中国汉族HHT家系的致病基因定位在ALK-1染色体区域。     

一个中国汉族先天性附耳表型致病基因的定位研究

目的定位一个中国汉族先天性面部畸形家系附耳表型的致病基因。方法通过全基因组扫描、连锁分析和单体型分析用微卫星遗传标记在染色体区域定位致病基因。结果全基因组扫描和连锁分析发现,附耳的致病基因可能定位于d18s462～d18s70之间,遗传距离为6.00cM,LODZMAX=1.83（d18s462,θ=0.06）;或者d7s2546～d7s559之间,遗传距离为8.94cM,LODZMAX=2.74（d7s2546,θ=0.05）。再经过单体型分析将其致病基因定位在d7s2546～d7s550之间,遗传距离为5.38cM。结论这个中国汉族家系附耳表型的致病基因定位d7s2546～d7s550之间,在染色体的位置为7q36.1～q36.2。     

遗传性釉质发育不全家系致病基因的定位研究

目的定位遗传性釉质发育不全（AI）家系的致病基因。方法收集1个常染色体显性AI家系,提取该家系19名成员（其中患者9例）的外周血DNA,选择横跨釉蛋白基因、成釉蛋白基因、釉丛蛋白基因、基质金属蛋白酶基因、丝氨酸蛋白酶基因5个候选基因的短串联重复序列（STR）,进行PCR扩增,经变性聚丙烯酰胺凝胶电泳确定基因型,并进行连锁分析。结果得到19名个体的8个STR位点的基因型,分别为D1s498、D1s2343、D4s1543、D4s2361、D4s2969、D11s1339、mmp20、D19s246。连锁分析结果显示各位点的LOD值在重组率为0时均小于1,不支持该家系的致病基因与5个侯选基因上的STR位点的连锁关系。结论连锁分析结果不支持该家系致病基因定位于已知基因座处,提示至少某些常染色体显性AI家系的致病基因不是文献所报道的AI候选基因,进一步证实了常染色体显性遗传性釉质发育不全的遗传异质性。     

基底细胞痣综合征中国一家系致病相关基因连锁及突变分析

目的 揭示基底细胞痣综合征中国一个家系发病的分子遗传基础，为家系中的年轻患者实行早期监测和治疗。方法 首先选择家系中先证者和其患病母亲及家系中一名健康人，提取外周血DNA，聚合酶链反应（PCR）扩增PTCH基因编码氨基酸的23个外显子，对扩增产物进行DNA测序后；采用位于9q22．3-q31区的3个微卫星DNA标记对该家系行遗传连锁分析。结果 先证者患病母亲PTCH基因未发现突变；先证者（V4）14号外显子发生同义突变；连锁分析显示，在位点D9S283、D9S1690和D9S1677，Lod值＜-2（θ=0．00）。结论 排除了PTCH基因作为基底细胞痣综合征该家系致病基因的可能。     

牙本质发育不全Ⅱ型的遗传异质性研究

目的：明确牙本质涎磷蛋白(dentin sialophosphoprotein，DSPP)是否为该家系的致病基因，并对该家系做进一步的基因定位研究。方法：通过DNA测序方法对DSPP基因进行突变检测，用位于4q21区域的7个微卫星位点对家系进行遗传连锁分析。结果：测序结果显示DSPP在该家系中不存在突变，基因定位研究表明致病基因在该家系位于IMS1534和DSPP之间。结论：DSPP在该家系不是致病基因，牙本质发育不全Ⅱ型存在遗传异质性。     

遗传性乳光牙本质家系致病基因的染色体定位

目的　研究一个在天津塘沽地区发现的遗传性乳光牙本质回族家系致病基因是否与染色体 4q2 1连锁。方法　提取该家系 1 3名成员的外周血DNA ,选择染色体 4q2 1上的 8个短串联重复序列多态性标记 (shorttandemrepeatpolymorphisms ,STRPs)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 8个STRPs的连锁关系。结果　得到 1 3名个体 8个位点的基因型和单体型 ,连锁分析结果显示 :8个STRPs的最大lod值均大于 0 ,其中 5个STRPs的lod值大于 1。结论　该家系致病基因定位在染色体 4q2 1上 ,表明中国回族人和报道的欧美人的DGI Ⅱ的基因座位是一致的     

遗传性牙本质发育不全Ⅱ型家系致病基因的连锁分析及DMP1的突变检测

目的：对中国江苏淮阴一个遗传性牙本质发育不全Ⅱ型家系的致病基因进行定位,同时对该疾病的侯选基因之一DMP1进行突变检测。方法：用位于4q21区域的7个微卫星位点对家系进行遗传连锁分析,并通过聚合酶链反应－单链构象多态分析（PCR－SSCP）和DNA测序方法对DMP1基因进行突变检测。结果：所选的7个位点,除D4S451和D4S1534之外,最大Lod值Zmax均大于3（θ＝0）;PCR－SSCP和测序结果显示DMP1Exon2－6均无突变。结论：遗传性牙本质发育不全Ⅱ型与位于4q21区域的微卫星位点GATA62A11、DSP、DMP1、SPP1和D4S1563连锁;排除DMP1做为该病致病基因的可能性。     

釉质发育不全临床表型与基因变异

釉质发育不全为一组引起釉质在数量、结构和组成上发生改变的遗传性疾病,临床表型多样,遗传方式有X-连锁、常染色体显性及隐性等多种形式,存在明显的临床和遗传异质性。本文就其临床分型、基因定位、致病基因以及候选基因的研究作一综述。     

中国汉族人群侵袭性牙周炎遗传方式初探

目的 初步探讨中国汉族人群侵袭性牙周炎( aggressive periodontitis,AgP)可能的遗传方式.方法 采用医学遗传数理统计方法中的分离分析方法(先验法+理论子女总数校正法)及多基因遗传的Edwards法对73个中国汉族人群AgP家系资料进行遗传方式分析.结果 AgP同胞患病率与一般人群AgP患病率的比值接近1/√q(q为人群患病率),符合多基因遗传;先验法结果显示将所有家系作为一个整体进行分析符合常染色体隐性遗传,理论子女总数校正后的分离率为0.2419,分离比接近常染色体隐性遗传模式的理想分离率0.25;x2测验法的结果同时显示亲代为重度牙周炎患者的家系有常染色体显性遗传的可能性.结论 本组中国汉族人AgP在遗传方式上存在异质性,常染色体隐性遗传方式占优势,但是亲代为重度慢性牙周炎患者的家系存在常染色体显性遗传的可能,提示AgP可能是存在着主效基因控制的复杂性疾病.     

非综合征性唇腭裂与MSX1基因传递不平衡研究

目的探讨MSX1基因与湖南汉族人群非综合征性唇腭裂（nonsyndromic cleft lip and palate，NSCLP）遗传易感性的关系。方法以MSX1基因内含子区的CA重复微卫星作为遗传标记，采用聚合酶链式反应（polymerase chain reaction，PCR）-变性聚丙烯酰胺凝胶（polyacrylamide gel electrophoresis，PAGE）基因分型技术对湖南汉族129个NSCLP核心家系387名成员进行基因型分析，并行传递不平衡检验（transmission disequilibrium test，TDT）及Logistic回归分析。结果TDT分析显示，MSX1基因CA4等位基因在唇裂伴（不伴）腭裂（cleft lip with or without palate，CL／P）和单纯性腭裂（cleft palate only，CPO）组均被优势传递给患病后代（P=0．018，P=0．041）。Logistic回归分析结果支持隐性遗传模式，CA4本身或其作为一致病基因的遗传标志以隐性遗传模式被遗传（P=0．009）。结论MSX1基因与湖南汉族人群NSCLP相关联，可能是其易感基因或与之存在连锁不平衡。     

New mutation of the patched homologue 1 gene in a Chinese family with naevoid basal cell carcinoma syndrome

Naevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is inherited in an autosomal dominant mode characterised by a combination of developmental anomalies and a predisposition to form tumours. Our aim was to search for patched homologue 1 (PTHC1) mutations in a Chinese family with NBCCS. Mutation analysis of PTCH1 was done of all 10 members of this family by amplified polymerase chain reaction and direct sequencing. Two novel PTCH1 mutations (3146A→T, 1686C→T) were identified in all five affected members. The mutation, 3146A→T in exon 17, is predicted to lead to different PTCH protein translations. 1686C→T mutation in exon 11 is a nonsense mutation. These mutations were not found in any unaffected members of this family or in 100 unrelated healthy Chinese people. Our findings suggest that the 3146A→T mutation in the PTCH gene may be the cause of NBCCS by affecting the conformation and function of the PTCH protein.     

Exclusion of candidate genes in two families with autosomal dominant hypocalcified amelogenesis imperfecta

The amelogenesis imperfectas (AI) are a group of hereditary enamel defects characterized by clinical and genetic diversity. The most common AI types are inherited as autosomal traits. Three mutations of the enamelin (ENAM) gene have been found in cases of autosomal dominant hypoplastic AI. The gene(s) responsible for hypocalcified forms of AI have not been identified, although a number of autosomal genes have been proposed as candidates for AI based on their expression by ameloblasts, including ameloblastin and enamelin (chromosome 4q13.3), tuftelin (chromosome 1q21), enamelysin (chromosome 11q22.3-q23) and kallikrein 4 (chromosome 19q13.3-q13.4). To localize the gene(s) responsible for autosomal dominant hypocalcified AI, we evaluated support for/against linkage of AI to genetic markers spanning five AI candidate genes in two extended families. Our data excluded all proposed candidate gene regions as causal for autosomal dominant hypocalcified AI in these families. These linkage findings provide further evidence for genetic heterogeneity among families with autosomal dominant AI and indicate that, at least, some forms of autosomal dominant hypocalcified AI are not caused by a gene in the five most commonly reported AI candidate genes.     

Nevoid basal cell carcinoma syndrome: a 17‐year study of 19 cases in Iranian population (1991–2008)

J Oral Pathol Med (2010) 39 : 677–680 Background: Nevoid basal cell carcinoma syndrome (NBCCS) is a hereditary autosomal dominant disorder with a wide range of clinical signs and symptoms. The major criteria are more than two basal cell carcinoma, keratocystic odontogenic tumor, three or more palmar pits, and calcification of the falx cerebri, spine and rib anomalies, and a family history of the syndrome. Methods: This study reports 19 cases in an Iranian population and presents this rare syndrome as a differential diagnosis of skeletal anomalies. Between 1991 and 2008, the demographic, clinical, radiologic and histologic data of 19 patients with NBCCS were analyzed. Results: The average age at the time of diagnosis of NBCCS was 35.12 years. All patients had a minimum of two major criteria. The major criteria with the most frequency were the keratocysts odontogenic tumor (19 patients), and the average number was 6.2. Basal cell carcinoma (8 patients), and the average number was 14.7 calcification of the falx cerebri (17 patients), palmo‐plantar pits (14 patients), mild hypertelorism (10 patients), and bilateral cleft lip and palate (1 patient). Only one patient was affected with an unusual case of NBCCS in a 30‐year‐old man with an associated squamous cell carcinoma of the maxillary sinus. Only two cases of this unusual association have been reported. This case is one of a large family including 14 NBCCS‐affected patients.     

PTCH1 and SMO gene alterations in keratocystic odontogenic tumors

Keratocystic odontogenic tumors (KCOTs, previously known as odontogenic keratocysts) are aggressive jaw lesions that may occur in isolation or in association with nevoid basal cell carcinoma syndrome (NBCCS). Mutations in the PTCH1 (PTCH) gene are responsible for NBCCS and are related in tumors associated with this syndrome. Mutations in the SMO gene have been identified in basal cell carcinoma and in medulloblastoma, both of which are features of NBCCS. To clarify the role of PTCH1 and SMO in KCOTs, we undertook mutational analysis of PTCH1 and SMO in 20 sporadic and 10 NBCCS-associated KCOTs, and for SMO, 20 additional cases of KCOTs with known PTCH1 status were also included. Eleven novel (1 of which occurred twice) and 5 known PTCH1 mutations were identified. However, no pathogenic mutation was detected in SMO. Our findings suggest that mutations are rare in SMO, but frequent in PTCH1 in sporadic and NBCCS-associated KCOTs. Abbreviations: NBCCS, nevoid basal cell carcinoma syndrome; KCOTs, keratocystic odontogenic tumors; BCCs, basal cell carcinomas.     

One germline mutation of PTCH gene in a Chinese family with non-syndromic keratocystic odontogenic tumours

Keratocystic odontogenic tumours (KOCTs) are common benign cystic tumours that arise sporadically or associated with nevoid basal cell carcinoma syndrome (NBCCS). PTCH mutation can be found in sporadically or NBCCS associated KOCTs. Few PTCH mutations in families with non-syndromic KOCTs have been reported. Through PCR and gene sequence analysis, the authors discovered one missense mutation c.3277G>C in exon 19 of PTCH gene in a Chinese family with non-syndromic KOCTs. This mutation causes one highly conserved glycine residue transit to arginine on the 10th transmembrane region of PTCH protein. This work revealed that the missense mutation of PTCH is the causative and dominant gene of KOCTs in this family.     

Further evidence of genetic heterogeneity segregating with hereditary gingival fibromatosis

Aim: To clinically characterize and map the disease-associated locus in a five-generation Chinese family with autosomal dominant early-onset hereditary gingival fibromatosis (HGF).
Material and Methods: A complete oral examination was conducted. Genomic DNA samples were obtained from 14 individuals. Short tandem repeats markers, which encompass four previously known loci related to HGF, were genotyped. Two-point log of the odds (LOD) scores were calculated using MLINK program of the LINKAGE software, multipoint and non-parametric linkage (NPL) analysis were performed using the GENEHUNTER software.
Results: Clinical evaluation and histological examination of this family suggested typical features of HGF. The onset age was early in the generations, ranging between 1 and 2 years. None of the tested markers showed cosegregation among affected individuals. Genotyping data from four putative regions yielded significant negative two-point LOD scores (<−2.0) at θ=0. The maximum multipoint LOD scores and NPL analysis revealed exclusion of these loci as well.
Conclusions: Exclusion of linkage in this family to any of the known HGF loci proved the existence of a novel locus for autosomal dominant HGF and showed that this rare disorder is far more heterogeneous than previously expected.