家族性腺瘤性息肉病(familial adenomatous polyposis,FAP)Ⅰ型[MIM:175100]、胃腺癌和胃近端息肉病(gastric adenocarcinoma and proximal polyposis of the stomach,GAPPS)[MIM:619182]均表现为常染色体显性遗传。这些疾病均由APC基...家族性腺瘤性息肉病(familial adenomatous polyposis,FAP)Ⅰ型[MIM:175100]、胃腺癌和胃近端息肉病(gastric adenocarcinoma and proximal polyposis of the stomach,GAPPS)[MIM:619182]均表现为常染色体显性遗传。这些疾病均由APC基因的致病变异引起,并统称为APC相关性息肉病。本文报道了1例中年女性患者,包括其临床资料、基因型检测及家系基因分析。患者的主要临床表现为剑突下、左下腹及下腹压痛和反跳痛,并伴有恶心、呕吐、腹部饱满及肠鸣音减弱。患者具有家族遗传特征,其母亲和舅舅均因结肠癌去世。我们使用一代高通量测序对患者的基因进行测序,结果显示,患者携带c.1974_1975del(p.Asn659Glnfs*14)变异,这是APC基因编码区因非三倍数碱基缺失导致的移码变异。此外,该APC基因致病变异目前未在大规模人群频率数据库gnomAD中报道。文献报道在家族性腺瘤性息肉病患者中曾检测到该变异(PMID:10094547)。APC基因型检测证实了该患者携带的是尚未在国内外大规模文献中报道的杂合子突变(chr5:112173265-112173266)。本报道为临床工作者提供了宝贵的临床资料,并促进了APC相关息肉病的研究进展。展开更多
Adenomatous polyposis coli(APC)mutations are the most frequently identified genetic alteration in sporadic colorectal cancer(CRC)cases,and a myriad of genetically engineered Apc-mutant CRC mouse models have been devel...Adenomatous polyposis coli(APC)mutations are the most frequently identified genetic alteration in sporadic colorectal cancer(CRC)cases,and a myriad of genetically engineered Apc-mutant CRC mouse models have been developed using various genetic manipulation techniques.The advent of the CRISPR/Cas9 system has revolutionized the field of genetic engineering and facilitated the development of new genetically engineered mouse models.In this study,we aimed to develop a novel Apc knockout allele using the CRISPR/Cas9 system and evaluate the phenotypic effects of this new allele in two different mouse strains.For this purpose,exon 16 of mouse Apc gene was targeted with a single-guide RNA,and the mouse carrying an Apc frameshift mutation at codon 750(^(Δ750))was chosen as the founder.The mutant FVB-Apc^(Δ750)mice were backcrossed with wild-type C57BL/6 mice,and the phenotypic effects of the knockout allele were evaluated in F8-FVB-Apc^(Δ750),F4-B6;FVB-Apc^(Δ750),and F1-B6;FVB-Apc^(Δ750)by a macroscopic and microscopic examination of the gastrointestinal system.The result showed that the mean polyp number was significantly higher in F4-BL6;FVB-Apc^(Δ750)than in F8-FVB-Apc^(Δ750).Intestinal polyposis was more prominent in F4-BL6;FVB-Apc^(Δ750),whereas a higher number of colon polyps than intestinal polyps were observed in F8-FVB-Apc^(Δ750).Additionally,F1-BL6;FVB-Apc^(Δ750)mixed background mice developed gastric polyps that morphologically resembled the pyloric gland adenoma of humans.In conclusion,we developed a novel CRISPR-mediated Apc knockout allele using two mouse strains.We showed that this allele can exert a strainspecific effect on the phenotype of mice and can cause gastric polyp formation.展开更多
文摘家族性腺瘤性息肉病(familial adenomatous polyposis,FAP)Ⅰ型[MIM:175100]、胃腺癌和胃近端息肉病(gastric adenocarcinoma and proximal polyposis of the stomach,GAPPS)[MIM:619182]均表现为常染色体显性遗传。这些疾病均由APC基因的致病变异引起,并统称为APC相关性息肉病。本文报道了1例中年女性患者,包括其临床资料、基因型检测及家系基因分析。患者的主要临床表现为剑突下、左下腹及下腹压痛和反跳痛,并伴有恶心、呕吐、腹部饱满及肠鸣音减弱。患者具有家族遗传特征,其母亲和舅舅均因结肠癌去世。我们使用一代高通量测序对患者的基因进行测序,结果显示,患者携带c.1974_1975del(p.Asn659Glnfs*14)变异,这是APC基因编码区因非三倍数碱基缺失导致的移码变异。此外,该APC基因致病变异目前未在大规模人群频率数据库gnomAD中报道。文献报道在家族性腺瘤性息肉病患者中曾检测到该变异(PMID:10094547)。APC基因型检测证实了该患者携带的是尚未在国内外大规模文献中报道的杂合子突变(chr5:112173265-112173266)。本报道为临床工作者提供了宝贵的临床资料,并促进了APC相关息肉病的研究进展。
基金The Scientific and Technological Research Council of Turkey 1001 program,Grant/Award Number:SBAG-215S926。
文摘Adenomatous polyposis coli(APC)mutations are the most frequently identified genetic alteration in sporadic colorectal cancer(CRC)cases,and a myriad of genetically engineered Apc-mutant CRC mouse models have been developed using various genetic manipulation techniques.The advent of the CRISPR/Cas9 system has revolutionized the field of genetic engineering and facilitated the development of new genetically engineered mouse models.In this study,we aimed to develop a novel Apc knockout allele using the CRISPR/Cas9 system and evaluate the phenotypic effects of this new allele in two different mouse strains.For this purpose,exon 16 of mouse Apc gene was targeted with a single-guide RNA,and the mouse carrying an Apc frameshift mutation at codon 750(^(Δ750))was chosen as the founder.The mutant FVB-Apc^(Δ750)mice were backcrossed with wild-type C57BL/6 mice,and the phenotypic effects of the knockout allele were evaluated in F8-FVB-Apc^(Δ750),F4-B6;FVB-Apc^(Δ750),and F1-B6;FVB-Apc^(Δ750)by a macroscopic and microscopic examination of the gastrointestinal system.The result showed that the mean polyp number was significantly higher in F4-BL6;FVB-Apc^(Δ750)than in F8-FVB-Apc^(Δ750).Intestinal polyposis was more prominent in F4-BL6;FVB-Apc^(Δ750),whereas a higher number of colon polyps than intestinal polyps were observed in F8-FVB-Apc^(Δ750).Additionally,F1-BL6;FVB-Apc^(Δ750)mixed background mice developed gastric polyps that morphologically resembled the pyloric gland adenoma of humans.In conclusion,we developed a novel CRISPR-mediated Apc knockout allele using two mouse strains.We showed that this allele can exert a strainspecific effect on the phenotype of mice and can cause gastric polyp formation.
