Aceto Gitana, Curia Maria Cristina, Veschi Serena, De Lellis Laura, Mammarella Sandra, Catalano Teresa, Stuppia Liborio, Palka Giandomenico, Valanzano Rosa, Tonelli Francesco, Casale Vincenzo, Stigliano Vittoria, Cetta Francesco, Battista Pasquale, Mariani-Costantini Renato, Cama Alessandro
Department of Oncology and Neurosciences, University G. D'Annunzio, Chieti, Italy.
Hum Mutat. 2005 Oct;26(4):394. doi: 10.1002/humu.9370.
The analysis of APC and MYH mutations in adenomatous polyposis coli patients should provide clues about the genetic heterogeneity of the syndrome in human populations. The entire coding region and intron-exon borders of the APC and MYH genes were analyzed in 60 unrelated Italian adenomatous polyposis coli patients. APC analysis revealed 26 point mutations leading to premature termination, one missense variant and one deletion spanning the entire coding region in 32 unrelated patients. Novel truncating point mutations included c.1176_1177insT (p.His393_PhefsX396), c.1354_1355del (p.Val452_SerfsX458), c.2684C>A (p.Ser895X), c.2711_2712del (p.Arg904_LysfsX910), c.2758_2759del (p.Asp920_CysfsX922), c.4192_4193del (p.Ser1398_SerfsX1407), c.4717G>T (p.Glu1573X) and a novel cryptic APC exon 6 splice site. MYH analysis revealed nine different germline variants in nine patients, of whom five were homozygotes or compound heterozygotes. The mutations included 4 novel MYH missense variants (c.692G>A, p.Arg231His; c.778C>T, p.Arg260Trp; c.1121T>C, p.Leu374Pro; and c.1234C>T, p.Arg412Cys) affecting conserved amino acid residues in the ENDO3c or NUDIX domains of the protein and one novel synonymous change (c.672C>T, p.Asn224Asn). Genotype-phenotype correlations were found in carriers of APC mutations but not in carriers of biallelic MYH mutations, except for a negative correlation with low number of polyps. A distinctive characteristic of patients negative for APC and MYH mutations was a significantly (p<0.0001) older age at diagnosis compared to patients with APC mutations. Moreover, the proportion of cases with an attenuated polyposis phenotype was higher (p = 0.0008) among patients negative for APC and MYH mutations than among carriers of APC or biallelic MYH mutations.
对家族性腺瘤性息肉病（adenomatous polyposis coli，APC）患者的APC和MYH基因突变进行分析，应能为该综合征在人群中的遗传异质性提供线索。我们对60例不相关的意大利家族性腺瘤性息肉病患者的APC和MYH基因的整个编码区及内含子-外显子边界进行了分析。APC分析显示，在32例不相关患者中，有26个导致过早终止的点突变、1个错义变异和1个跨越整个编码区的缺失。新的截短点突变包括c.1176_1177insT（p.His393_PhefsX396）、c.1354_1355del（p.Val452_SerfsX458）、c.2684C>A（p.Ser895X）、c.2711_2712del（p.Arg904_LysfsX910）、c.2758_2759del（p.Asp920_CysfsX922）、c.4192_4193del（p.Ser1398_SerfsX1407）、c.4717G>T（p.Glu1573X）以及一个新的APC基因第6外显子隐匿性剪接位点。MYH分析在9例患者中发现了9种不同的种系变异，其中5例为纯合子或复合杂合子。这些突变包括4个新的MYH错义变异（c.692G>A，p.Arg231His；c.778C>T，p.Arg260Trp；c.1121T>C，p.Leu374Pro；以及c.1234C>T，p.Arg412Cys），影响该蛋白ENDO3c或NUDIX结构域中的保守氨基酸残基，还有1个新的同义变化（c.672C>T，p.Asn224Asn）。在APC突变携带者中发现了基因型-表型相关性，但在双等位基因MYH突变携带者中未发现，除了与息肉数量少呈负相关。与APC突变患者相比，APC和MYH突变均为阴性的患者诊断时年龄显著更大（p<0.0001）。此外，APC和MYH突变均为阴性的患者中，息肉病表型减弱的病例比例高于APC或双等位基因MYH突变携带者（p = 0.0008）。
