Mutational analysis of Portuguese families with multiple endocrine neoplasia type 1 reveals large germline deletions
Mutational analysis of Portuguese families with multiple endocrine neoplasia type 1 reveals large germline deletions
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DOI：
10.1046/j.1365-2265.2002.01505.x
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发表时间：
2002-04-01
影响因子：
3.2
通讯作者：
Leite, V
中科院分区：
文献类型：
--
作者：
Cavaco, BM;Domingues, R;Leite, V
目的确定葡萄牙激酶中MEN 1基因突变谱，并鉴定突变携带者。患者、设计与结果采用单链构象多态性（SSCP）和MEN 1基因编码区和外显子-内含子边界的DNA序列分析方法，对6个不相关的MEN 1家系进行MEN 1基因突变研究。这些方法在四个家族中鉴定了4种不同的杂合突变：两种突变是新的（mt 1539 delG和mt 655 ims 11 bp），两种先前已观察到（mt 735 del 46 p和mt 1656 del C），所有突变均导致提前终止密码子。在剩下的两个家族中，没有检测到突变或异常MEN 1转录本，5'基因内标记D11 S4946和外显子9的密码子418多态性的分离研究揭示了MEN 1基因的两个大的种系缺失。Southern印迹和肿瘤杂合性缺失分析证实并细化了这些缺失的限制，其至少跨越MEN 1基因：在一个家族中，从外显子7到3'非翻译区，在另一个家族中，从5'多态性位点D11 S4946到外显子9（消除起始密码子）。26 muplatin基因携带者被确定，其中6人是symptomatic.CONCLUSIONS这些结果强调的重要性，检测MEN 1种系缺失的患者谁没有突变的编码区。通过使用基因内多态性D11 S4946和密码子418的分离研究可以获得指示这种缺失存在的重要线索。这些突变的检测将有助于在葡萄牙MEN 1家庭的临床管理的遗传咨询。
OBJECTIVE To determine the spectrum of MEN1 mutations in Portuguese kindreds, and identify mutation-carriers.PATIENTS, DESIGN AND RESULTS Six unrelated MEN1 families were studied for MEN1 gene mutations by single-strand conformational polymorphism (SSCP) and DNA sequence analysis of the coding region and exon-intron boundaries of the MEN1 gene. These methods identified 4 different heterozygous mutations in four families: two mutations are novel (mt 1539 delG and mt 655 ims 11 bp) and two have been previously observed (mt 735 del 46p and mt 1656 del C) all resulting in a premature stop codon. In the remaining two families, in whom no mutations or abnormal MEN1 transcripts were detected, segregation studies of the 5' intragenic marker D11S4946 and codon 418 polymorphism in exon 9 revealed two large germline deletions of the MEN1 gene. Southern blot and tumour loss of heterozygosity analysis confirmed and refined the limits of these deletions, which spanned the MEN1 gene at least from: exon 7 to the 3' untranslated region, in one family, and the 5' polymorphic site D11S4946 to exon 9 (obliterating the initiation codon), in the other family. Twenty-six mutant-gene carriers were identified, 6 of which were asymptomatic.CONCLUSIONS These results emphasize the importance of the detection of MEN1 germline deletions in patients who do not have mutations of the coding region. Important clues indicating the presence of such deletions may be obtained by segregation studies using the intragenic polymorphisms D11S4946 and at codon 418. The detection of these mutations will help in the genetic counselling of clinical management of the MEN1 families in Portugal.