家族性腺瘤性息肉病家系中一种新的APC基因的胚系突变

目的研究1个家族性腺瘤性息肉病家系的腺瘤样息肉病基因（adenomatous polyposis coli，APC）的胚系突变。方法经结肠镜、组织病理学检查和家族史的调查，确定了1例家族性腺瘤性息肉病（familial adenomatous polyposis，FAP）患者。应用多重连接依赖性探针扩增（multiplex ligation-dependent probe amplification，MLPA）、变性高效液相色谱（denaturing high-performance liquid chromatography，DHPLC）测序等技术对这一家系的成员进行系统的APC全基因筛查。结果在此家系中发现一个新的APC基因的胚系突变c。1999 C〉T（Q667X），这一突变造成了APC基因终止密码子的形成，从而形成有功能障碍的截短蛋白。临床上，此突变可引起严重的FAP症状，早发结直肠腺瘤和腺癌。结论Q667X胚系突变是引起该家系临床表型的原因，受累成员可考虑大肠预防性切除手术。     

APC mutation associated with late onset of familial adenomatous polyposis.

Familial adenomatous polyposis is an autosomal dominantly inherited disorder. Mutation studies in the corresponding gene (APC) may provide information for predictive tests for persons at risk in affected families. We report here a new mutation in exon 6 (codon 233) of the APC gene and clinical data in a large family with late onset of the disease in most affected persons.     

APC mutation and phenotypic spectrum of Singapore familial adenomatous polyposis patients

Familial adenomatous polyposis (FAP) is a familial form of colon cancer caused by mutation of the adenomatous polyposis coli (APC) gene. Although the APC gene has been extensively studied in the Caucasian population, it has not been previously described in the Chinese population. In the present study, we investigated APC mutation and phenotypic spectrum in the Singapore FAP families who are predominantly Chinese. The protein truncation test (PTT) was used to screen the entire APC gene for germline mutations in 28 unrelated families. Fifteen different mutations were identified in 22 families. Eight mutations were 1-11 basepair deletions or insertions; three involved deletions of whole exons and four were nonsense mutations. Nine of the mutations, including two complex rearrangements, are novel. Eight families including three de novo cases have the same (AAAGA) deletion at codon 1309, indicating that like the Western families, codon 1309 is also the mutation 'hot spot' for Singapore FAP families. In contrast, we did not find any mutation in codon 1061, the second hot spot for the Western population. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is consistently associated with the prescribed domain (codons 463 to 1387) and is the only phenotype with no intra-family variation. Other than CHRPE, differences in the type and frequency of extracolonic manifestations within the FAP families suggest the influence of modifying genes and environmental factors.     

APC intragenic haplotypes in familial adenomatous polyposis

Genetic epidemiological studies are useful for the knowledge of the association of markers and genes involved in diseases. In the present work, we studied the frequency of four adenomatous polyposis coli intragenic RFLP markers often used in risk evaluation in a population of 10 familial adenomatous polyposis patients from 10 unrelated Portuguese familial adenomatous polyposis families not sharing the same mutation, and in a population of 55 unrelated healthy Portuguese volunteers. We compared the frequency obtained to normal and affected populations and to results already reported in other populations. We observed allelic frequencies for the Portuguese population that agree with the published ones. The intragenic polymorphisms show strong gametic disequilibrium suggesting little recombination between them. We observed haplotype frequencies significantly different in patients and controls. The gametic disequilibrium may be due to a common founder for a proportion of apparently unrelated probands.     

中国人家族性腺瘤性患肉病患者结肠腺瘤性患肉病基因的胚系突变

目的 探讨中国人家族性腺瘤性息肉病(familial adenomatous polyposis,FAr)患者的结肠腺瘤性息肉病(adenomatous polyposis coli,APC)基因的胚系突变类型.方法 对9个FAP家系18名成员进行多重连接依赖性探针扩增(multiplex ligation-dependent probe amplification,MLPA)检测APC基因有无大片段缺失.再应用PCR扩增APC基因的15个外显子区域,经变性高效液相色谱(denaturing high performance liquid chromatography,DHPLC)对每个扩增片段进行筛查,流出峰异常的片段,经DNA测序验证小片段的改变.结果 9个家系中有3个家系发现有APC基因的胚系突变:家系2为c.3184-3187 del CAhA,家系4为c.5432C＞T,家系9为c.3925-3929 del AAAAG.3种突变中c.5432C＞T在数据库中未见报道.结论 中国人不同的APC基因的胚系突变可引起FAP;无APC胚系突变的FAP患者的发病可能存在其他的机制.     

Novel mutations of the APC gene in familial adenomatous polyposis in Greek patients

Familial adenomatous polyposis (FAP), a premalignant clinical entity inherited as an autosomal dominant trait, is characterized by the development thousands of adenomatous polyps of the colorectum during the 2nd and 3rd decade of life. Approximately 80% of patients with FAP harbor truncating germline mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. We tested 24 members of six Greek families. All patients had the FAP phenotype, and one patient had an extracolonic tumor (medulloblastoma). Our method for testing was the polymerase chain reaction (PCR) amplification from genomic DNA extracted from whole blood, followed by automated DNA sequencing. Two novel truncating mutations (2601delGA and R923X) and three already-known mutations (R876X, Q1045X, and D1822V) were found. Other polymorphisms were also found. We identified the inactivating APC mutation in 12 of 13 of our FAP patients. Our results suggest that PCR sequencing is a reliable method for screening the APC gene for germline mutations.     

家族性腺瘤样息肉病中APC基因的胚系突变分析

目的 探索有效的突变检测技术，系统分析家族性腺瘤样息肉病(familial adenomatous polyposis，FAP)相关基因结肠腺瘤病(adenomatous polyposis coli，APC)基因的胚系突变，及其与疾病表型的关系。方法 从22例临床确诊的FAP患者，外周静脉血中提取基因组DNA。变性高效液相色谱、蛋白截短检测、测序技术结合应用进行全基因分析。根据患者临床资料，进行基因型-表型分析。结果 22例FAP患者中13例检出APC基因胚系突变，均为无义或移码突变。基因型-表型关系的初步分析表明，在基因5′端或3′端发生突变的患者临床症状较轻，在基因中段发生突变的患者临床症状典型或严重。结论 本研究中所采用的技术体系可敏感、高效地检出APC基因突变，APC基因的突变型与FAP患者的临床表型存在关联，所采用的技术体系适用于FAP症状出现前的基因诊断。     

Mutation analysis of the adenomatous polyposis coli (APC) gene in Danish patients with familial adenomatous polyposis (FAP)

Development of one hundred or more adenomas in the colon and rectum is diagnostic for the dominantly inherited, autosomal disease Familial Adenomatous Polyposis (FAP). It is possible to identify a mutation in the Adenomatous Polyposis Coli (APC) gene in approximately 80% of the patients, and almost 1,000 different pathogenic mutations have been identified in the APC gene up till now. We report 12 novel and 24' previously described germline APC mutations from 48 unrelated Danish families. Four families with the mutation localized in the 3' region of the gene showed great variance in phenotypic presentation.     

Seven novel mutations in the APC gene of Portuguese families with familial adenomatous polyposis: correlation with phenotype.

Germ-line mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP). In the present study, we have used the protein truncation test to screen for mutations in exon 15 and exons 1-14 of the APC gene and denaturing gradient gel electrophoresis to analyze exons 1-14. We have studied nine unrelated FAP kindreds, eight with the classical phenotype and one with an atypical phenotype, with several family members exhibiting fewer than 50 colonic polyps. The combined use of these two methodologies allowed the identification of seven novel mutations, with two unrelated families sharing the same mutation. All mutations were chain terminating: six resulted from small deletions, one from a small insertion, and one was a point mutation, resulting in a premature stop codon. Seven mutations were located in exon 15 of the APC gene, one was in exon 10, and the remaining one, which corresponded to the kindred with an atypical phenotype, was located in exon 4.     

APC mutations in familial adenomatous polyposis families in the Northwest of England

We have investigated a series of FAP patients in the Northwest of England in order to identify and characterise the specific APCmutations. Using SSCP, we found 27 mutations in a total of 50 families investigated. The mutations were predominantly frameshift or nonsense mutations and there were two splice site changes. We have described two patients with severe Gardner's phenotype from different ethnic backgrounds who share the same mutation at codon 1537. Although the frequency of the most common mutation appears low, it is not dissimilar to that reported by other groups. Hum Mutat 10:376–380, 1997. © 1997 Wiley-Liss, Inc.     

Frequency of common and novel inactivating APC mutations in 202 families with familial adenomatous polyposis

In the course of presymptomatic diagnosis in families with familialadenomatous polyposis (FAP) we screened 202 unrelated patientsfor mutations in the 20.8% of the index patients by a singlestep screening procedure based on heteroduplex analysis of aPCR product encompassing codons 1027–1384 of the APC gene.The most common mutations in our sample were a 5 bp deletionat codon 1309 in 9% of the familles, a5 bp deletion at codon1061 in 5% and a 4 bp deletion at codon 1068 in 2.5% of thefamilies. In addition, 11 novel mutations localized within theexons 11–15 of the APC gene were identified by the heteroduplexor SSCP methods.     

Mutations of the APC adenomatous polyposis coli) gene

Several investigators have reported germline mutations of the APC gene in patients with familial adenomatous polyposis (FAP) as well as somatic mutations in tumors developed in digestive organs (stomach, pancreas, colon, and rectum). Those results provide evidence that inactivation of the APC gene plays a significant role in FAP and in sporadic tumors of these tissues. APC mutations have led to some interesting observations. First, the great majority of the mutations found to date would result in truncation of the APC product. Second, almost all the mutations have occurred within the first half of the coding sequence, and somatic mutations in colorectal tumors are further clustered in a particular region called MCR (mutation cluster region). Third, most identified point mutations in the APC gene are transitions from cytosine to other nucleotides. Fourth, the location of germ-line mutations tends to correlate with the number of colorectal polyps in FAP patients. Furthermore, inactivation of both alleles of the APC gene seems to be required as an early event to develop most of adenomas and carcinomas in the colon and rectum as well as some of those in the stomach. © 1993 Wiley-Liss, Inc.