Juvenile polyposis syndrome is a rare autosomal dominant syndrome characterized by multiple distinct juvenile polyps in the gastrointestinal tract and an increased risk of colorectal cancer.The cumulative life-time ri...Juvenile polyposis syndrome is a rare autosomal dominant syndrome characterized by multiple distinct juvenile polyps in the gastrointestinal tract and an increased risk of colorectal cancer.The cumulative life-time risk of colorectal cancer is 39% and the relative risk is 34.Juvenile polyps have a distinctive histology characterized by an abundance of edematous lamina propria with inflammatory cells and cystically dilated glands lined by cuboidal to columnar epithelium with reactive changes.Clinically,juvenile polyposis syndrome is defined by the presence of 5 or more juvenile polyps in the colorectum,juvenile polyps throughout the gastrointestinal tract or any number of juvenile polyps and a positive family history of juvenile polyposis.In about 50%-60% of patients diagnosed with juvenile polyposis syndrome a germline mutation in the SMAD4 or BMPR1A gene is found.Both genes play a role in the BMP/TGF-beta signalling pathway.It has been suggested that cancer in juvenile polyposis may develop through the socalled "landscaper mechanism" where an abnormal stromal environment leads to neoplastic transformation of the adjacent epithelium and in the end invasive carcinoma.Recognition of this rare disorder is important for patients and their families with regard to treatment,follow-up and screening of at risk individuals.Each clinician confronted with the diagnosis of a juvenile polyp should therefore consider the possibility of juvenile polyposis syndrome.In addition,juvenile polyposis syndrome provides a unique model to study colorectal cancer pathogenesis in general and gives insight in the molecular genetic basis of cancer.This review discusses clinical manifestations,genetics,pathogenesis and management of juvenile polyposis syndrome.展开更多
Cre/loxP technology has been widely used to study cell type-specific functions of genes. Proper interpretation of such data critically depends on a clear understanding of the tissue specificity of Cre expression. The ...Cre/loxP technology has been widely used to study cell type-specific functions of genes. Proper interpretation of such data critically depends on a clear understanding of the tissue specificity of Cre expression. The Dmpl- Cre mouse, expressing Cre from a 14-kb DNA fragment of the mouse Dmpl gene, has become a common tool for studying gene function in osteocytes, but the presumed cell specificity is yet to be fully established. By using the Ai9 reporter line that expresses a red fluorescent protein upon Cre recombination, we find that in 2-month-old mice, Dmpl-Cre targets not only osteocytes within the bone matrix but also osteoblasts on the bone surface and preosteoblasts at the metaphyseal chondro-osseous junction. In the bone marrow, Cre activity is evident in certain stromal cells adjacent to the blood vessels, but not in adipocytes. Outside the skeleton, Dmpl-Cre marks not only the skeletal muscle fibers, certain cells in the cerebellum and the hindbrain but also gastric and intestinal mesenchymal cells that express Pdgfra. Confirming the utility of Dmpl-Cre in the gastrointestinal mesenchyme, deletion of Bmprla with Dmpl-Cre causes numerous large polyps along the gastrointestinal tract, consistent with prior work involving inhibition of BMP signaling. Thus, caution needs to be exercised when using Dmpl-Cre because it targets not only the osteoblast lineage at an earlier stage than previously appreciated, but also a number of non-skeletal cell types.展开更多
Background Bone morphogenetic protein receptor type 1A(BMPR1A)is responsible for two individual Mendelian diseases:juvenile polyposis syndrome and hereditary mixed polyposis syndrome 2,which have overlapping phenotype...Background Bone morphogenetic protein receptor type 1A(BMPR1A)is responsible for two individual Mendelian diseases:juvenile polyposis syndrome and hereditary mixed polyposis syndrome 2,which have overlapping phenotypes.This study aimed to elucidate whether these two syndromes are just two subtypes of a single syndrome rather than two isolated syndromes.Methods We sequenced the BMPR1A gene in 186 patients with polyposis and colorectal cancer,and evaluated the clinicopathological features and phenotypes of the probands and their available relatives with BMPR1A mutations.Results BMPR1A germline mutations were found in six probands and their three available relatives.The numbers of frameshift,nonsense,splice-site,andmissensemutations were one,one,two,and two,respectively;two of the sixmutations were novel.Typical juvenile polyps were found in only three patients.Two patients had colorectal cancer rather than any polyps.Conclusions Diseases in BMPR1A germline mutation carriers vary from mixed polyposis to sole colorectal cancer,and typical juvenile polyps do not always occur in these carriers.The variety of phenotypes reflected the features of BMPR1Amutation carriers,which should be recognized as a spectrum of one syndrome.Genetic testing may be a good approach to identifying BMPR1A-related syndromes.展开更多
骨形态发生蛋白受体1B(Bone morphogenetic protein receptor 1B,BMPR1B)是一种重要的跨膜受体蛋白,主要参与转化生长因子β(TGF-β)通路,其在调控成骨分化、细胞扩散以及卵巢卵泡发育等过程中起重要作用,并直接影响如绵羊等动物的繁殖...骨形态发生蛋白受体1B(Bone morphogenetic protein receptor 1B,BMPR1B)是一种重要的跨膜受体蛋白,主要参与转化生长因子β(TGF-β)通路,其在调控成骨分化、细胞扩散以及卵巢卵泡发育等过程中起重要作用,并直接影响如绵羊等动物的繁殖性状。绵羊BMPR1B基因发生A746G突变(命名为FecB突变),导致第249位氨基酸由谷氨酰胺(Q)转变为精氨酸(R),进而使得绵羊排卵数和产羔数显著增加,因此BMPR1B成为目前最受关注的绵羊多羔主效基因。论文就绵羊BMPR1B基因定位、功能机制研究进展及其对高繁殖力绵羊的影响进行了综述,同时也对BMPR1B功能研究中一些亟待解决的问题展开了讨论。展开更多
文摘Juvenile polyposis syndrome is a rare autosomal dominant syndrome characterized by multiple distinct juvenile polyps in the gastrointestinal tract and an increased risk of colorectal cancer.The cumulative life-time risk of colorectal cancer is 39% and the relative risk is 34.Juvenile polyps have a distinctive histology characterized by an abundance of edematous lamina propria with inflammatory cells and cystically dilated glands lined by cuboidal to columnar epithelium with reactive changes.Clinically,juvenile polyposis syndrome is defined by the presence of 5 or more juvenile polyps in the colorectum,juvenile polyps throughout the gastrointestinal tract or any number of juvenile polyps and a positive family history of juvenile polyposis.In about 50%-60% of patients diagnosed with juvenile polyposis syndrome a germline mutation in the SMAD4 or BMPR1A gene is found.Both genes play a role in the BMP/TGF-beta signalling pathway.It has been suggested that cancer in juvenile polyposis may develop through the socalled "landscaper mechanism" where an abnormal stromal environment leads to neoplastic transformation of the adjacent epithelium and in the end invasive carcinoma.Recognition of this rare disorder is important for patients and their families with regard to treatment,follow-up and screening of at risk individuals.Each clinician confronted with the diagnosis of a juvenile polyp should therefore consider the possibility of juvenile polyposis syndrome.In addition,juvenile polyposis syndrome provides a unique model to study colorectal cancer pathogenesis in general and gives insight in the molecular genetic basis of cancer.This review discusses clinical manifestations,genetics,pathogenesis and management of juvenile polyposis syndrome.
基金supported by NIH grants AR060456 and AR055923(FL)supported by NIH DK105129,DK094989,by DK052574 to the Washington University Digestive Core Centers(DDRCC)+6 种基金by the pre-Program Project Award from the Siteman Cancer Center Investment Programsupported by the NIGMS cell and Molecular Biology Training Grant(GM007067)supported by the NIH funded George O’Brien Center for Kidney Disease Research(P30DK079333)Kidney translational Research Core and the Renal Division at the Washington University School of Medicinesupported by the Alafi Neuroimaging Laboratorythe Hope Center for Neurological DisordersNIH Shared Instrumentation Grant(S10 RR0227552)to Washington University
文摘Cre/loxP technology has been widely used to study cell type-specific functions of genes. Proper interpretation of such data critically depends on a clear understanding of the tissue specificity of Cre expression. The Dmpl- Cre mouse, expressing Cre from a 14-kb DNA fragment of the mouse Dmpl gene, has become a common tool for studying gene function in osteocytes, but the presumed cell specificity is yet to be fully established. By using the Ai9 reporter line that expresses a red fluorescent protein upon Cre recombination, we find that in 2-month-old mice, Dmpl-Cre targets not only osteocytes within the bone matrix but also osteoblasts on the bone surface and preosteoblasts at the metaphyseal chondro-osseous junction. In the bone marrow, Cre activity is evident in certain stromal cells adjacent to the blood vessels, but not in adipocytes. Outside the skeleton, Dmpl-Cre marks not only the skeletal muscle fibers, certain cells in the cerebellum and the hindbrain but also gastric and intestinal mesenchymal cells that express Pdgfra. Confirming the utility of Dmpl-Cre in the gastrointestinal mesenchyme, deletion of Bmprla with Dmpl-Cre causes numerous large polyps along the gastrointestinal tract, consistent with prior work involving inhibition of BMP signaling. Thus, caution needs to be exercised when using Dmpl-Cre because it targets not only the osteoblast lineage at an earlier stage than previously appreciated, but also a number of non-skeletal cell types.
基金supported by National Key R&D Program of China[no.2017YFC1308800]National Natural Science Foundation of China[no.81870455]Discipline Climbing Program 234 of Changhai Hospital[no.2019YXK036].
文摘Background Bone morphogenetic protein receptor type 1A(BMPR1A)is responsible for two individual Mendelian diseases:juvenile polyposis syndrome and hereditary mixed polyposis syndrome 2,which have overlapping phenotypes.This study aimed to elucidate whether these two syndromes are just two subtypes of a single syndrome rather than two isolated syndromes.Methods We sequenced the BMPR1A gene in 186 patients with polyposis and colorectal cancer,and evaluated the clinicopathological features and phenotypes of the probands and their available relatives with BMPR1A mutations.Results BMPR1A germline mutations were found in six probands and their three available relatives.The numbers of frameshift,nonsense,splice-site,andmissensemutations were one,one,two,and two,respectively;two of the sixmutations were novel.Typical juvenile polyps were found in only three patients.Two patients had colorectal cancer rather than any polyps.Conclusions Diseases in BMPR1A germline mutation carriers vary from mixed polyposis to sole colorectal cancer,and typical juvenile polyps do not always occur in these carriers.The variety of phenotypes reflected the features of BMPR1Amutation carriers,which should be recognized as a spectrum of one syndrome.Genetic testing may be a good approach to identifying BMPR1A-related syndromes.
文摘骨形态发生蛋白受体1B(Bone morphogenetic protein receptor 1B,BMPR1B)是一种重要的跨膜受体蛋白,主要参与转化生长因子β(TGF-β)通路,其在调控成骨分化、细胞扩散以及卵巢卵泡发育等过程中起重要作用,并直接影响如绵羊等动物的繁殖性状。绵羊BMPR1B基因发生A746G突变(命名为FecB突变),导致第249位氨基酸由谷氨酰胺(Q)转变为精氨酸(R),进而使得绵羊排卵数和产羔数显著增加,因此BMPR1B成为目前最受关注的绵羊多羔主效基因。论文就绵羊BMPR1B基因定位、功能机制研究进展及其对高繁殖力绵羊的影响进行了综述,同时也对BMPR1B功能研究中一些亟待解决的问题展开了讨论。
文摘【目的】利用生物信息学软件对绵羊BMPR1B基因进行分析,并了解其功能和结构,为进一步探讨BMPR1B基因在绵羊生长繁殖以及绵羊卵泡生长和分泌和产羔率等研究奠定遗传信息基础.【方法】利用生物信息学对绵羊骨形态发生蛋白1β(bone morphogenetic protein 1beta,BMPR1B)基因的蛋白理化性质、亚细胞定位、潜在信号肽剪切位点、蛋白跨膜螺旋结构、糖基化和磷酸化位点、蛋白保守结构域、亲疏水性和编码产物进行功能预测分析,及其编码蛋白的二级结构和三级结构等进行分析预测.【结果】绵羊BMPR1B基因CDs编码蛋白质的502个氨基酸残基中,带电荷氨基酸、疏水氨基酸和极性氨基酸含量较高.相对分子量为56 907.4U,理论等电点pI为7.78;亚细胞主要定位于细胞核,不属于分泌蛋白;无信号肽序列;预测含有32个磷酸化位点和2个糖基化位点;存在一段跨膜结构且分别有一个GS和S-TKc的结构域,二级结构以无规卷曲为主.预测该蛋白在翻译和脂肪代谢过程中有着重要意义.【结论】绵羊BMPR1B蛋白包含502个氨基酸,为细胞核合成蛋白,该蛋白翻译后修饰的主要方式是磷酸化,在细胞内主要行翻译和脂肪代谢作用.蛋白二级结以无规卷曲为主,三级结构主要由α螺旋和无规卷曲缠绕折叠形成.
文摘为了探寻影响杜寒杂交羊体尺性状的遗传标记,试验通过Multiplex SNaPshot技术对72只6月龄杜寒杂交羊的HMGA1、HMGA2、PLAG1和BMPR1B四个影响体型大小的候选基因中的20个SNPs位点进行了基因型分型,应用PLINK v1.07软件对单核苷酸多态性(SNPs)位点与体尺性状(体斜长、体高和管围)进行单点关联分析,利用Excel软件进行等位基因替代效应分析,并应用HaploView version 4.2软件进行单倍型构建及连锁不平衡分析。结果表明:除2个SNPs位点外,其他18个SNPs位点均存在突变基因型。HMGA1基因上游的rs405972023位点与体斜长和管围呈显著相关(P<0.05),rs404165907位点与体斜长呈显著相关(P<0.05);HMGA2基因第2内含子区域的rs399648873位点和该基因上游rs409565324位点与体高呈显著相关(P<0.05);位于PLAG1和BMPR1B基因及其周边区域的SNPs位点与杜寒杂交羊体尺性状未呈现显著相关(P>0.05)。HMGA1基因rs405972023位点TT基因型个体的体斜长极显著高于CT基因型个体(P<0.01),rs404165907位点AA基因型个体的体斜长显著高于CA和CC基因型个体(P<0.05)。HMGA1基因中的4个SNPs位点呈现强连锁,共构建出4种单倍型频率大于0.03的单倍型组合,TCAA、CTCG、TTAG、TTCG单倍型频率分别为0.479,0.318,0.096,0.071。说明rs404165907与rs405972023位点是可用于杜寒杂交羊体斜长育种的潜在分子标记。
