Alternative titles; symbols
HGNC Approved Gene Symbol: SMAD2
Cytogenetic location: 18q21.1 Genomic coordinates (GRCh38): 18:47,808,957-47,930,872 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q21.1 | Congenital heart defects, multiple types, 8, with or without heterotaxy | 619657 | Autosomal dominant | 3 |
| Loeys-Dietz syndrome 6 | 619656 | Autosomal dominant | 3 |
Riggins et al. (1996) identified a homolog of the Drosophila 'mothers against decapentaplegic' (Mad) gene (also 'mothers against dpp'). The predicted 467-amino acid polypeptide, which the authors called JV18-1, shows maximal homology to Mad genes at the amino and carboxy termini of the protein, with 62% identity to Mad over 373 amino acids. Drosophila Mad apparently acts downstream of the TGF-beta receptor (190181) to transduce signals from the members of the TGF-beta gene family (190180). The gene product shows 44% identity over 158 amino acids to another Mad homolog, DPC4 (SMAD4; 600993).
Graff et al. (1996) described a family of Xenopus proteins homologous to the Drosophila Mad and C. elegans CEM genes. MAD and MAD-related proteins are important components of the serine/threonine kinase receptor signal transduction pathways. Eppert et al. (1996) cloned and characterized a member of this family, which they designated MADR2. The gene encodes a 467-amino acid protein that contains no common structural motifs known at that time. MADR2 shares high homology with MADR1 (601595) and significant homology with DPC4. They reported that MADR2 is rapidly phosphorylated by activation of the TGF-beta signaling pathway.
By RT-PCR of human erythroleukemia cell mRNA using primers based on conserved regions between the Drosophila Mad and C. elegans Sma genes, Nakao et al. (1997) cloned a SMAD2 cDNA. Northern blot analysis of human tissues detected ubiquitously expressed 3.4- and 2.9-kb SMAD2 transcripts. The encoded protein has a molecular mass of 58 kD by SDS-PAGE.
Baker and Harland (1996) identified the mouse Madr2 gene using a functional assay to clone mouse mesoderm inducers from Xenopus ectoderm. The mouse amino acid sequence is 46% identical to the human tumor suppressor DPC4. Madr2 was expressed widely in the mouse embryo (with the exception of heart and the tail bud) from embryonic days 6.5 to 10.5. Madr2 was found to be confined to the nucleus in the deep anterior cells of the second axis, whereas it was localized in the cytoplasm in the epidermal and more posterior cells. Because Madr2 localized to the nucleus in response to activin (see 147290) and because activin-like phenotypes were induced by overexpression of Madr2, Baker and Harland (1996) concluded that Madr2 is a signal transduction component that mediates the activity of activin.
Macias-Silva et al. (1996) demonstrated that MADR2 and not the related protein DPC4 transiently interacts with the TGF-beta receptor and is directly phosphorylated by the complex on C-terminal serines. Interaction of MADR2 with receptors and phosphorylation requires activation of receptor I by receptor II and is mediated by the receptor I kinase. Mutation of the phosphorylation sites generated a dominant-negative MADR2 that blocks TGF-beta-dependent transcriptional responses, stably associates with receptors, and fails to accumulate in the nucleus in response to TGF-beta signaling. Thus, Macias-Silva et al. (1996) concluded that transient association and phosphorylation of MADR2 by the TGF-beta receptor is necessary for nuclear accumulation and initiation of signaling.
SMAD proteins mediate TGF-beta signaling to regulate cell growth and differentiation. Stroschein et al. (1999) identified SnoN (165340) as a component of the SMAD pathway. They proposed a model of regulation of TGF-beta signaling by SnoN in which SnoN maintains the repressed state of TGF-beta target genes in the absence of ligand and participates in the negative feedback regulation of TGF-beta signaling. In the absence of TGF-beta, SnoN binds to the nuclear SMAD4 (DPC4) and represses TGF-beta-responsive promoter activity through recruitment of a nuclear repressor complex. TGF-beta induces activation and nuclear translocation of SMAD2, SMAD3 (603109), and SMAD4. SMAD3 causes degradation of SnoN, allowing a SMAD2/SMAD4 complex to activate TGF-beta target genes. To initiate a negative feedback mechanism that permits a precise and timely regulation of TGF-beta signaling, TGF-beta also induces an increased expression of SnoN at a later stage, which in turn binds to SMAD heteromeric complexes and shuts off TGF-beta signaling.
SMADs mediate activin, TGF-beta, and BMP signaling from receptors to nuclei. According to the current model, activated activin/TGF-beta receptors phosphorylate the carboxyl-terminal serines of SMAD2 and SMAD3 (SSMS-COOH); phosphorylated SMAD2/SMAD3 oligomerizes with SMAD4, translocates to the nucleus, and modulates transcription of defined genes. To test key features of this model, Funaba and Mathews (2000) explored the construction of constitutively active SMAD2 mutants. To mimic phosphorylated SMAD2, they made 2 SMAD2 mutants with acidic amino acid substitutions of carboxyl-terminal serines: SMAD2-2E and SMAD2-3E. The mutants enhanced basal transcriptional activity in a mink lung epithelial cell line, L17. In a SMAD4-deficient cell line, SMAD2-2E did not affect basal signaling; suggesting that the constitutively active SMAD2 mutant also requires SMAD4 for function. Funaba and Mathews (2000) concluded that SMAD2 phosphorylation results in both tighter binding to SMAD4 and increased nuclear concentration; those changes may be responsible for transcriptional activation by SMAD2.
You and Kruse (2002) studied corneal myofibroblast differentiation and signal transduction induced by the TGFB family members activin A (147290) and bone morphogenetic protein-7 (BMP7; 112267). They found that activin A induced phosphorylation of SMAD2, and BMP7 induced SMAD1 (601595), both of which were inhibited by follistatin (136470). Transfection with antisense SMAD2/SMAD3 prevented activin-induced expression and accumulation of alpha-smooth muscle actin. The authors concluded that TGFB proteins have different functions in the cornea. Activin A and TGFB1, but not BMP7, are regulators of keratocyte differentiation and might play a role during myofibroblast transdifferentiation. SMAD2/SMAD3 signal transduction appeared to be important in the regulation of muscle-specific genes.
Oft et al. (2002) found that activation of Smad2 induced migration of mouse squamous carcinoma cells, but that elevated levels of H-ras (190020) were required for nuclear accumulation of Smad2. Elevated levels of both were required for induction of spindle-cell transformation and metastasis.
SMAD2 is released from cytoplasmic retention by TGFB receptor-mediated phosphorylation and accumulates in the nucleus, where it associates with cofactors to regulate transcription. Xu et al. (2002) uncovered direct interactions of SMAD2 with the nucleoporins NUP214 (114350) and NUP153 (603948). These interactions mediate constitutive nucleocytoplasmic shuttling of SMAD2. NUP214 and NUP153 compete with the cytoplasmic retention factor SARA (603755) and the nuclear SMAD2 partner FAST1 (603621) for binding to a hydrophobic corridor on the MH2 surface of SMAD2. TGFB receptor-mediated phosphorylation stimulates nuclear accumulation of SMAD2 by modifying its affinity for SARA and SMAD4 but not for NUP214 or NUP153. Thus, by directly contacting the nuclear pore complex, SMAD2 undergoes constant shuttling, providing a dynamic pool that is competitively drawn by cytoplasmic and nuclear signal transduction partners.
TGFB stimulation leads to phosphorylation and activation of SMAD2 and SMAD3, which form complexes with SMAD4 that accumulate in the nucleus and regulate transcription of target genes. Inman et al. (2002) demonstrated that following TGFB stimulation of epithelial cells, receptors remain active for at least 3 to 4 hours, and continuous receptor activity is required to maintain active SMADs in the nucleus and for TGFB-induced transcription. Continuous nucleocytoplasmic shuttling of the SMADs during active TGFB signaling provides the mechanism whereby the intracellular transducers of the signal continuously monitor receptor activity. These data explain how, at all times, the concentration of active SMADs in the nucleus is directly dictated by the levels of activated receptors in the cytoplasm.
Using Xenopus embryo explants, whole zebrafish embryos, and mammalian cell lines, Batut et al. (2007) showed that phosphorylation and nuclear accumulation of Smad2 required an intact microtubule network and the ATPase activity of the kinesin motor. Smad2 interacted directly with the kinesin-1 light chain subunit (KLC2), and interfering with kinesin activity in Xenopus and zebrafish embryos phenocopied loss of Nodal (601265) signaling.
Davis et al. (2008) demonstrated that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta (190180) and BMPs is mediated by miR21 (611020). miR21 downregulates PDCD4 (608610), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-beta and BMP signaling promoted a rapid increase in expression of mature miR21 through a posttranscriptional step, promoting the processing of primary transcripts of miR21 (pri-miR21) into precursor miR21 (pre-miR21) by the Drosha complex (see 608828). TGF-beta and BMP-specific SMAD signal transducers SMAD1, SMAD2, SMAD3 (603109), and SMAD5 (603110) are recruited to pri-miR21 in a complex with the RNA helicase p68 (DDX5; 180630), a component of the Drosha microprocessor complex. The shared cofactor SMAD4 (600993) is not required for this process. Thus, Davis et al. (2008) concluded that regulation of microRNA biogenesis by ligand-specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4-independent responses mediated by the TGF-beta and BMP signaling pathways.
Bertero et al. (2018) described the interactome of SMAD2/3 in human pluripotent stem cells. This analysis revealed that SMAD2/3 is involved in multiple molecular processes in addition to its role in transcription. In particular, Bertero et al. (2018) identified a functional interaction with the METTL3 (612472)-METTL14 (616504)-WTAP (605442) complex, which mediates the conversion of adenosine to N6-methyladenosine (m6A) on RNA. Bertero et al. (2018) showed that SMAD2/3 promotes binding of the m6A methyltransferase complex to a subset of transcripts involved in early cell fate decisions. This mechanism destabilizes specific SMAD2/3 transcriptional targets, including the pluripotency factor gene NANOG (607937), priming them for rapid downregulation upon differentiation to enable timely exit from pluripotency. Bertero et al. (2018) concluded that their findings revealed the mechanism by which extracellular signaling can induce rapid cellular responses through regulation of the epitranscriptome. They commented that these aspects of TGF-beta signaling could have far-reaching implications in many other cell types and in diseases such as cancer.
Crystal Structure
Wu et al. (2000) determined the crystal structure of a SMAD2 MH2 domain in complex with the SMAD-binding domain of SARA at 2.2-angstrom resolution.
Wu et al. (2001) determined the crystal structure of a phosphorylated SMAD2 at 1.8-angstrom resolution. The structure revealed the formation of a homotrimer mediated by the C-terminal phosphoserine residues. The phosphoserine-binding surface on the MH2 domain, which is frequently targeted for inactivation in cancers, is highly conserved among the comediator SMADs (Co-SMADs) and receptor-regulated SMADs (R-SMADs). This finding, together with mutagenesis data, pinpointed a functional interface between SMAD2 and SMAD4. In addition, the phosphoserine-binding surface on the MH2 domain coincides with the surface on R-SMADs that is required for docking interactions with the serine-phosphorylated receptor kinases. These observations defined a bifunctional role for the MH2 domain as a phosphoserine-X-phosphoserine-binding module in receptor ser/thr kinase signaling pathways.
Takenoshita et al. (1998) determined the structure of the human MADH2 gene and characterized the 5-prime and 3-prime ends of MADH2 mRNAs. The MADH2 gene contains 12 exons, the first 2 (1a and 1b) of which are alternatively spliced such that they are used singly or in combination. In addition, RT-PCR showed that the fourth exon (exon 3), which encodes 30 amino acids, is spliced out in about 10% of MADH2 transcripts. The authors found that MADH2 mRNAs are transcribed from 2 different promoters located in 1 CpG island. The 3-prime ends of MADH2 mRNAs are heterogeneous, and Takenoshita et al. (1998) identified several polyadenylation signals.
Eppert et al. (1996) mapped the MADR2 gene close to DPC4 at 18q21, a region which is frequently deleted in colorectal cancers. Riggins et al. (1996) mapped the human MADH2 gene to 18q21. Nakao et al. (1997) refined the localization of the SMAD2 gene to 18q21.1, approximately 3 Mb proximal to DPC4, by fluorescence in situ hybridization.
Congenital Heart Defects, Multiple Types 8, With or Without Heterotaxy
From a cohort of 362 parent-offspring trios in which a child had severe congenital heart disease but no first-degree relative with structural heart disease, Zaidi et al. (2013) identified 2 unrelated patients with congenital heart defects and heterotaxy (CHTD8; 619657) who were heterozygous for de novo mutations in the SMAD2 gene: a splice site variant (601366.0001) and a missense variant (W244C; 601366.0002), respectively.
Using GeneMatcher, Granadillo et al. (2018) identified 3 patients with complex congenital heart defects, including 1 with heterotaxy, who had heterozygous mutations in the SMAD2 gene, including a nonsense mutation (Q159X; 601366.0007), a missense mutation (C312S; 601366.0008), and a splice site mutation (601366.0009). The authors concluded that mutation in SMAD2 results in 2 distinct phenotypes: a cardiac phenotype with complex congenital defects, with or without heterotaxy, and a vascular phenotype characterized by adult-onset arterial aneurysms and features suggestive of a connective tissue disorder (Loeys-Dietz syndrome).
Loeys-Dietz Syndrome 6
In a cohort of 365 patients with arterial aneurysm and/or dissection, who were 60 years of age or younger and negative for mutation in the FBN1 (134797), TGFBR1 (190181), TGFBR2 (190182), ACTA2 (102620), or MYH11 (160745) genes, Micha et al. (2015) sequenced the SMAD2 gene and identified 2 probands with heterozygous missense mutations that were not found in public variant databases: L449S (601366.0003) and G457R (601366.0004), respectively. Analysis of exome data from 211 families with thoracic aortic aneurysm identified another SMAD2 missense variant (Q388R; 601366.0005) in 2 affected sisters.
By whole-exome sequencing in a 51-year-old Chinese man with thoracic and abdominal aortic aneurysm, Zhang et al. (2017) identified heterozygosity for a missense mutation in the SMAD2 gene (A278V; 601366.0006) that was not found in public variant databases.
In a 42-year-old woman with aortic root aneurysm and dilated and tortuous cerebral arteries, Granadillo et al. (2018) identified heterozygosity for a 1-bp duplication in the SMAD2 gene (601366.0010) that was not found in public variant databases.
Cannaerts et al. (2019) identified heterozygous SMAD2 mutations in 9 patients from 5 unrelated families with thoracic aortic aneurysm and/or arterial tortuosity and connective tissue and skeletal anomalies (see, e.g., 601366.0010 and 601366.0011).
Somatic Mutation in Colorectal Cancer
In a screen of 66 sporadic colorectal carcinomas, Eppert et al. (1996) identified 4 missense mutations in MADR2, 2 of which were associated with loss of heterozygosity (LOH) in 1 allele. These mutations were associated with loss of protein expression or loss of TGF-beta-regulated phosphorylation. Eppert et al. (1996) proposed that MADR2 is a tumor suppressor gene and that mutations acquired in colorectal cancer may function to disrupt TGF-beta signaling.
Riggins et al. (1996) evaluated JV18-1 in a panel of 18 colorectal cancer cell lines, each containing allelic loss of the minimally lost region on chromosome 18q. RT-PCR studies revealed JV18-1 expression in normal colon, normal brain, and in 17 of 18 colorectal tumors. They identified 1 tumor in which there was a homozygous deletion of JV18-1 sequences. The deletion in this tumor did not extend proximally to include D18S535 or distally to DPC4. In another tumor, a smaller protein encoded by JV18-1 was present. The protein was shorter because of a deletion extending from codons 345 to 358. This deletion was somatic in origin. Riggins et al. (1996) concluded that this gene family may be important in the suppression of neoplasia, since its members transduce growth inhibitory signals from TGF-beta.
By PCR-SSCP analysis of the entire coding region of the SMAD2 gene using intron-based primers, Takenoshita et al. (1998) screened genomic DNA sequences of colorectal cancers for mutations of the SMAD2 gene. Although no mutations were found within any exon of SMAD2, 2 of 60 sporadic colorectal cancers displayed deletions in the polypyrimidine tract preceding exon 4. Deletions of this region were also detected in colon cancer cell lines, and were clustered within cells exhibiting microsatellite instability. Deletions in the polypyrimidine tract had no effect on the splicing of the SMAD2 gene in these cases; however, the polypyrimidine tract in the splicing acceptor site may be a target for mutations in mismatch repair-deficient tumors.
Takagi et al. (1998) carried out mutation analyses of the SMAD2 gene on cDNA sampled from 36 primary colorectal cancer specimens. Only 1 missense mutation (2.8%), producing an amino acid substitution in the highly conserved region, and 2 homozygous deletions (5.5%) of the total coding region of SMAD2 gene were detected. They concluded that the SMAD2 gene may play a role as a candidate tumor suppressor gene in a small fraction of colorectal cancers. Even in combination with changes in SMAD4, the observed frequency was not sufficient to account for all 18q21 deletions in colorectal cancers. Thus, another tumor suppressor gene, such as DCC (120470), discovered as the first tumor suppressor candidate in the region, may exist in the 18q21 region where LOH is often seen.
Using cDNA, Roth et al. (2000) conducted mutation analysis of the SMAD2, SMAD3, and SMAD4 genes in 14 Finnish kindreds with hereditary nonpolyposis colon cancer (see 120435). They found no mutations.
Waldrip et al. (1998) studied the effect of Smad2 in mouse embryonic development by targeted disruption of the mouse Smad2 gene using embryonic stem cell technology. They found that Smad2 function was not required for mesoderm production per se, but, rather unexpectedly, in the absence of Smad2, the entire epiblast adopts a mesodermal fate giving rise to a normal yolk sac and fetal blood cells. In contrast, Smad2 mutant mouse embryos entirely lacked tissues of the embryonic germ layers. Waldrip et al. (1998) concluded that Smad2 signals serve to restrict the site of primitive streak formation and establish anterior-posterior identity within the epiblast. Chimera experiments demonstrated that these essential activities are contributed by the extraembryonic tissues. Thus, the extraembryonic tissues play critical roles in establishing the body plan during early mouse development.
Derynck et al. (1996) proposed a revised nomenclature for the Mad-related products and genes that are implicated in signal transduction by members of the TGF-beta family. As the root symbol they proposed SMAD, which is a merger of Sma (the gene in C. elegans) and Mad. SMAD serves to differentiate these proteins from unrelated gene products previously called MAD (see 600021). JV18.1 became SMAD2 in their nomenclature.
In a patient (1-02020) with complex congenital heart defects and heterotaxy (CHTD8; 619657), Zaidi et al. (2013) identified a heterozygous de novo splice site mutation in intron 6 of the SMAD2 gene (p.IVS6+1G-A). Cardiovascular anomalies in the proband included dextrocardia, unbalanced complete atrioventricular canal, pulmonary stenosis, double-outlet right ventricle, dextroposition of the great arteries, and atrial septal defect; she also had asplenia.
In a patient (1-02621) with complex congenital heart defects and heterotaxy (CHTD8; 619657), Zaidi et al. (2013) identified a heterozygous de novo missense mutation in the SMAD2 gene (trp244 to cys; W244C). Cardiovascular anomalies in the proband included dextrocardia, unbalanced right-dominant complete atrioventricular canal, pulmonary stenosis, left superior vena cava to left atrium, partial anomalous pulmonary venous return, and double-outlet right ventricle. She also exhibited abnormal nose, foot syndactyly, and gut malrotation.
In a 51-year-old woman (family 1) with Loeys-Dietz syndrome-6 (LDS6; 619656), Micha et al. (2015) identified heterozygosity for a c.1346T-C transition (c.1346T-C, NM_001003652.3) in the SMAD2 gene, resulting in a leu449-to-ser (L449S) substitution at a highly conserved residue within the MH2 domain. The mutation was not found in the 1000 Genomes Project, dbSNP137, ExAC, or NHLBI Go ESP databases. The proband had aneurysms and/or dissections of the left vertebral, internal carotid, and intracavernous carotid arteries, as well as bilateral dissection of the carotid arteries in the carotid canal and caliber changes of the left and right internal carotid arteries and left vertebral artery. CT of the thorax and abdomen revealed no aortic abnormalities; however, the proband's mother had thoracic and abdominal aneurysms as well as aortic tortuosity, and a maternal uncle died at age 50 due to dissection of the abdominal aorta. Familial segregation of the mutation was not reported.
In a 30-year-old woman (family 2) with Loeys-Dietz syndrome-6 (LDS6; 619656), Micha et al. (2015) identified heterozygosity for a c.1369G-A transition (c.1369G-A, NM_001003652.3) in the SMAD2 gene, resulting in a gly457-to-arg (G457R) substitution at a highly conserved residue within the MH2 domain. The mutation was not found in the 1000 Genomes Project, dbSNP137, ExAC, or NHLBI Go ESP databases. The proband was tall with long thin fingers, and had inguinal hernia repair and surgery for pes planus in childhood; at age 23, she was diagnosed with dilation of the aortic root and dural ectasia. Skeletal features included pain in multiple joints and mild scoliosis.
In 2 sisters with Loeys-Dietz syndrome-6 (LDS6; 619656), Micha et al. (2015) identified heterozygosity for a c.1163A-G transition (c.1163A-G, NM_001003652.3) in the SMAD2 gene, resulting in a gln388-to-arg (Q388R) substitution at a highly conserved residue within the MH2 domain. The mutation was not found in the 1000 Genomes Project, dbSNP137, ExAC, or NHLBI Go ESP databases. The sisters both had aneurysms of the ascending aorta, at ages 46 and 59 years, respectively, as well as striae and long toes. Other features included downslanting palpebral fissures, high-arched palate, and abdominal wall hernia. They also experienced joint pain and exhibited significant osteoarthritis, requiring replacement of some joints. Their mother died suddenly at age 56 of unknown cause, and their paternal grandfather was reported to have died at age 76 of aortic aneurysm.
In a 51-year-old Chinese man with thoracic and abdominal aortic aneurysm (LDS6; 619656), Zhang et al. (2017) identified heterozygosity for a c.833C-T transition (c.833C-T, NM_001003652.3) in exon 8 of the SMAD2 gene, resulting in an ala278-to-val (A278V) substitution at a highly conserved residue within the MH2 domain. The mutation, which was not found in the dbSNP139, 1000 Genomes Project, ESP, or ExAC databases, was also not present in the proband's mother, suggesting that he inherited it from his father, who died at age 40 of thoracic aortic aneurysm.
In a 2-year-old girl (patient 1) with complex congenital heart defects (CHTD8; 619657), Granadillo et al. (2018) identified heterozygosity for a c.475G-T transversion (c.475G-T, NM_005901.5) in exon 3 of the SMAD2 gene, resulting in a glu159-to-ter (E159X) substitution within the MH1 domain. The mutation, which was not found in the NHLBI ESP, ExAC, or gnomAD databases, was not present in the mother; the father was unavailable for testing. Cardiovascular defects in the proband included atrial and ventricular septal defect, double-outlet right ventricle, dextroposition of the great arteries, patent ductus arteriosus, and valvular anomalies. Because the proband also exhibited a single central incisor, analysis of a holoprosencephaly panel revealed a known HPE-associated variant (see HPE4, 142946) in the TGIF1 gene (Q107L; 602630.0006).
In a 10-year-old girl (patient 2) with complex congenital heart defects (CHTD8; 619657), Granadillo et al. (2018) identified heterozygosity for a de novo c.935G-C transition (c.935G-C, NM_005901.5) in exon 8 of the SMAD2 gene, resulting in a cys312-to-ser (C312S) substitution at a highly conserved residue within the beta strand of the MH2 domain. The mutation was not found in the NHLBI ESP, ExAC, or gnomAD databases. Cardiovascular defects in the proband included atrial and ventricular septal defect, double-outlet right ventricle, dextroposition of the great arteries, patent ductus arteriosus, and mitral and pulmonary valve atresia.
In a female fetus (patient 3) with complex congenital heart defects and heterotaxy (CHTD8; 619657), in whom no mutation was found in a panel of heterotaxy genes, Granadillo et al. (2018) identified heterozygosity for a de novo splice site mutation (c.237-12A-G, NM_005901.5) in intron 2 of the SMAD2 gene. RNA analysis revealed inclusion of 11 bp of intronic sequence before exon 3, causing a frameshift resulting in a premature termination codon (Thr80LeufsTer12). The splice variant was not found in the NHLBI ESP, ExAC, or gnomAD databases. Cardiovascular defects in the proband included dextrocardia, atrial isomerism, atrial and ventricular septal defect, unbalanced complete atrioventricular canal, hypoplastic left ventricle, and anomalous pulmonary venous return; she also had dextrogastria and left-sided gallbladder.
In a 42-year-old woman (patient 4) with aortic root aneurysm, bicuspid aortic valve, and dilated and tortuous cerebral arteries (LDS6; 619656), Granadillo et al. (2018) identified heterozygosity for a de novo 1-bp duplication (c.612dupT, NM_005901.5) in exon 5 of the SMAD2 gene, causing a frameshift resulting in a premature termination codon (asn205-to-ter, N205X).
In a 70-year-old father and his 30-year-old son (family1) with dilation of the aortic root, Cannaerts et al. (2019) identified heterozygosity for the 1-bp duplication in the SMAD2 gene resulting in introduction of the premature stop codon N205X. Both father and son exhibited tall stature and long fingers.
In a 51-year-old man (family 4) with spontaneous dissection of the left coronary artery, who also had tortuosity of the circle of Willis and iliac arteries (LDS6; 619656), Cannaerts et al. (2019) identified heterozygosity for a c.1082A-C transversion in the SMAD2 gene, resulting in an asn361-to-thr (N361T) substitution within the MH2 domain. The mutation was not found in his unaffected sister or sons; DNA from his deceased parents was unavailable. Other features in the proband included broad uvula, pes planus, pectus asymmetry, mild scoliosis, generalized arthralgias with tendinopathies, and inguinal hernia.
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