Identification of a novel <i>BMPR1A</i> germline mutation in a Korean juvenile polyposis patient without <i>SMAD4</i> mutation

Ij, Kim; Jh, Park; Hc, Kang; Kh, Kim; Kim, Jeehwan; Jl, Ku; Kang, S-B.; Sy, Park; Lee, Jae Sung; Park, JG

doi:10.1034/j.1399-0004.2003.00008.x

Cited by 21 publications

(20 citation statements)

References 18 publications

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“…Patient IV:76 had a splice-site variant c.230 + 2T > C (class 4), II:59 had a truncating variant, c.441delT, Phe147Leufs*18 (class 5) and the last patient (II:58) had a probable pathogenic (class 4) missense mutation, c.1409 C > T, p.Met470Thr in BMPR1A . This missense mutation has previously been found in a patient with a juvenile polyposis phenotype and around 300 polyps throughout the entire gastrointestinal tract [15]. Two patients from Group I, “CRC familial or unknown inheritance not polyposis”, had variants in AXIN2 .…”

Section: Resultsmentioning

confidence: 89%

Expanding the genotype–phenotype spectrum in hereditary colorectal cancer by gene panel testing

et al. 2016

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Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties linked to genotype-phenotype diversity and the benefits of using a gene panel. Pathogenicity classification was carried out on 46 detected variants. In total we detected sixteen pathogenic or likely pathogenic variants and 30 variants of unknown clinical significance. Four of the pathogenic or likely pathogenic variants were found in BMPR1A in patients with unexplained familial adenomatous polyposis or atypical adenomatous polyposis, which extends the genotype-phenotype spectrum for this gene. Nine patients had more than one variant remaining after the filtration, including three with truncating mutations in BMPR1A, PMS2 and AXIN2. CNVs were found in three patients, in upstream regions of SMAD4, MSH3 and CTNNB1, and one additional individual harbored a 24.2 kb duplication in CDH1 intron1.Electronic supplementary materialThe online version of this article (doi:10.1007/s10689-016-9934-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 89%

Expanding the genotype–phenotype spectrum in hereditary colorectal cancer by gene panel testing

et al. 2016

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“…In addition, Smad1 and Smad5, which are central components for transduction of BMP signals, are strongly downregulated in chemically induced mouse epidermal tumors (He et al, 2001), while in human basal cell carcinoma, R-Smad expression is also decreased (Lange et al, 1999). Moreover, germline mutations in BMPR1A correlate with a significant proportion of cases of juvenile polyposis with a risk for colon cancer (Howe et al, 2001;Zhou et al, 2001;Kim et al, 2003). On the other hand, constitutive activation of WNT/␤-catenin signaling can lead to cancer (reviewed in Taipale and Beachy, 2001).…”

Section: Role(s) Of Bmpr-ia Signaling In Hair Follicle Tumorigenesis:mentioning

confidence: 96%

Essential roles of BMPR‐IA signaling in differentiation and growth of hair follicles and in skin tumorigenesis

Kwan

Wang

et al. 2004

Genesis

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Hair differentiation and growth are controlled by complex reciprocal signaling between epithelial and mesenchymal cells. To better understand the requirement and molecular mechanism of BMP signaling in hair follicle development, we performed genetic analyses of bone morphogenetic protein receptor 1A (BMPR-IA) function during hair follicle development by using a conditional knockout approach. The conditional mutation of Bmpr1a in ventral limb ectoderm and its derivatives (epidermis and hair follicles) resulted in a lack of hair outgrowth from the affected skin regions. Mutant hair follicles exhibited abnormal morphology and lacked hair formation and pigment deposition during anagen. The timing of the hair cycle and the proliferation of hair matrix cells were also affected in the mutant follicles. We demonstrate that signaling via epithelial BMPR-IA is required for differentiation of both hair shaft and inner root sheath from hair matrix precursor cells in anagen hair follicles but is dispensable for embryonic hair follicle induction. Surprisingly, aberrant de novo hair follicle morphogenesis together with hair matrix cell hyperplasia was observed in the absence of BMPR-IA signaling within the affected skin of adult mutants. They developed hair follicle tumors from 3 months of age, indicating that inactivation of epidermal BMPR-IA signaling can lead to hair tumor formation. Taken together, our data provide genetic evidence that BMPR-IA signaling plays critical and multiple roles in controlling cell fate decisions or maintenance, proliferation, and differentiation during hair morphogenesis and growth, and implicate Bmpr1a as a tumor suppressor in skin tumorigenesis.

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“…When complexed, the constitutive kinase activity of the type II receptor transphosphorylates the type I GS domain, activating the type I receptor, which binds and phosphorylates primarily receptor-mediated Smad proteins (R-Smad) (Carcamo et al 1994;Wrana et al 1994;Chen et al 1998b;Macias-Silva et al 1998;Chen and Massague 1999). Mutations in the human type I receptors ALK1/ACVRL1, ALK2/ACVR1, ALK3/BMPR1A, ALK4/ACVR1B, ALK5/TGFbR1, and ALK6/BMPR1B have been identified and in each case are associated with a disease and/or developmental syndrome with very specific manifestations, e.g., hereditary hemorrhagic telangiectasia type 2 (HHT2) (ALK1/ACVRL1), fibrodysplasia ossificans progressiva (FOP) (ALK2/ ACVR1), juvenile polyposis syndrome (ALK3/BMPR1A), pancreatic adenocarcinoma (ALK4/ACVR1B), LoeysDietz syndrome (ALK5/TGFbR1), and brachydactyly type A2 (ALK6/BMPR1B) (Howe et al 2001;Su et al 2001;Zhou et al 2001;Kim et al 2003;Loeys et al 2005;Lehmann et al 2003Lehmann et al , 2006Abdalla and Letarte 2006;Bayrak-Toydemir et al 2006;Shore et al 2006;Wehner et al 2006;Olivieri et al 2007). In general, the specific effects of each mutation are not well understood in terms of signal transduction and functional consequences.…”

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confidence: 99%

Functional Analysis of saxophone, the Drosophila Gene Encoding the BMP Type I Receptor Ortholog of Human ALK1/ACVRL1 and ACVR1/ALK2

Twombly

Bangi

et al. 2009

Genetics

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In metazoans, bone morphogenetic proteins (BMPs) direct a myriad of developmental and adult homeostatic events through their heterotetrameric type I and type II receptor complexes. We examined 3 existing and 12 newly generated mutations in the Drosophila type I receptor gene, saxophone (sax), the ortholog of the human Activin Receptor-Like Kinase1 and -2 (ALK1/ACVRL1 and ALK2/ACVR1) genes. Our genetic analyses identified two distinct classes of sax alleles. The first class consists of homozygous viable gain-of-function (GOF) alleles that exhibit (1) synthetic lethality in combination with mutations in BMP pathway components, and (2) significant maternal effect lethality that can be rescued by an increased dosage of the BMP encoding gene, dpp 1. In contrast, the second class consists of alleles that are recessive lethal and do not exhibit lethality in combination with mutations in other BMP pathway components. The alleles in this second class are clearly loss-of-function (LOF) with both complete and partial loss-offunction mutations represented. We find that one allele in the second class of recessive lethals exhibits dominant-negative behavior, albeit distinct from the GOF activity of the first class of viable alleles. On the basis of the fact that the first class of viable alleles can be reverted to lethality and on our ability to independently generate recessive lethal sax mutations, our analysis demonstrates that sax is an essential gene. Consistent with this conclusion, we find that a normal sax transcript is produced by sax P , a viable allele previously reported to be null, and that this allele can be reverted to lethality. Interestingly, we determine that two mutations in the first class of sax alleles show the same amino acid substitutions as mutations in the human receptors ALK1/ACVRl-1 and ACVR1/ALK2, responsible for cases of hereditary hemorrhagic telangiectasia type 2 (HHT2) and fibrodysplasia ossificans progressiva (FOP), respectively. Finally, the data presented here identify different functional requirements for the Sax receptor, support the proposal that Sax participates in a heteromeric receptor complex, and provide a mechanistic framework for future investigations into disease states that arise from defects in BMP/TGF-b signaling.T HE type I serine-threonine receptors of the transforming growth factor-b (TGF-b)/bone morphogenetic protein (BMP) signaling pathway are critical for the transduction and specificity of signals initiated by the secreted ligands of this superfamily. A dimeric ligand elicits a vast range of biological responses by binding to the extracellular domain of a heterotetrameric receptor complex comprising two type I and two type II serine/threonine kinase receptors that then transduce a signal by phosphorylation of intracellular transcriptional regulators (reviewed by Yamashita et al. 1994;Weis-Garcia and Massague 1996; Kirsch et al. 2000a,b;Shi and Massague 2003; ten Dijke and Hill 2004). Both receptor types have a cysteine-rich, ligandbinding extracellular domain, ...

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Identification of a novel BMPR1A germline mutation in a Korean juvenile polyposis patient without SMAD4 mutation

Cited by 21 publications

References 18 publications

Expanding the genotype–phenotype spectrum in hereditary colorectal cancer by gene panel testing

Expanding the genotype–phenotype spectrum in hereditary colorectal cancer by gene panel testing

Essential roles of BMPR‐IA signaling in differentiation and growth of hair follicles and in skin tumorigenesis

Functional Analysis of saxophone, the Drosophila Gene Encoding the BMP Type I Receptor Ortholog of Human ALK1/ACVRL1 and ACVR1/ALK2

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