Alternative titles; symbols
HGNC Approved Gene Symbol: TGFBR1
Cytogenetic location: 9q22.33 Genomic coordinates (GRCh38): 9:99,103,647-99,154,192 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q22.33 | {Multiple self-healing squamous epithelioma, susceptibility to} | 132800 | Autosomal dominant | 3 |
| Loeys-Dietz syndrome 1 | 609192 | Autosomal dominant | 3 |
The TGFBR1 gene encodes a serine/threonine kinase receptor for transforming growth factor-beta (TGFB1; 190180). Most growth factor receptors are transmembrane tyrosine kinases or are associated with cytoplasmic tyrosine kinases. Another class of transmembrane receptors, however, is predicted to function as serine/threonine kinases. On the basis of their various biologic activities, different species of TGF-beta are probably potent developmental regulators of cell proliferation and differentiation. Several types of TGF-beta-binding proteins have been detected at the cell surface. Type I and type II receptors are defined on the basis of the mobility of their (125)I-TGF-beta cross-linked products in denaturing gels. These receptors probably mediate most activities of TGF-beta. The type II receptor (TGFBR2; 190182) functions as a transmembrane serine/threonine kinase and is required for the antiproliferative activity of TGF-beta, whereas the type I receptor mediates the induction of several genes involved in cell-matrix interactions (summary by Ebner et al., 1993).
Ebner et al. (1993) cloned a murine serine/threonine kinase receptor that shares a conserved extracellular domain with the type II TGF-beta receptor. Overexpression of this receptor alone did not increase cell surface binding of TGF-beta, but coexpression with the type II TGF-beta receptor caused TGF-beta to bind to this receptor, which had the size of the type I TGF-beta receptor. Overexpression of this newly cloned receptor inhibited binding of TGF-beta to the type II receptor in a dominant-negative fashion. Combinatorial interactions and stoichiometric ratios between the type I and II receptors may therefore determine the extent of TGF-beta binding and the resulting biologic activities.
By PCR analysis on human erythroleukemia cell cDNA using degenerate primers based on conserved regions of ser/thr kinase receptors, Franzen et al. (1993) isolated a cDNA encoding TGFBR1, which they called ALK5 (activin receptor-like kinase-5). The deduced 503-amino acid, 53-kD TGFBR1 ser/thr kinase contains a signal peptide; an extracellular cysteine-rich region with a single N-glycosylation site; a transmembrane region; and a putative cytoplasmic protein kinase domain. SDS-PAGE analysis showed that immunoprecipitation of TGFBR1 incubated with labeled TGFB1 produced a 70-kD complex as well as a heteromeric 94-kD TGFBR2 complex. Northern blot analysis detected a 5.5-kb TGFBR1 transcript in all tissues tested, with highest expression in placenta and lowest expression in brain and heart. Transient expression of TGFBR1 in a receptor-negative cell line led to the production of plasminogen activator inhibitor-1 (PAI1; 173360) in response to stimulation with TGFB1.
TGFB1 regulates cell cycle progression by a unique signaling mechanism that involves its binding to TGFBR2 and activation of TGFBR1. Both are transmembrane serine/threonine receptor kinases. The TGFBR1 receptor may be inactivated in many of the cases of human tumor cells refractory to TGFB-mediated cell cycle arrest. Vellucci and Reiss (1997) reported that the TGFBR1 gene is approximately 31 kb long and contains 9 exons. The organization of the segment of the gene that encodes the C-terminal portion of the serine/threonine kinase domain appears to be highly conserved among members of the gene family.
Johnson et al. (1995) used PCR with a hybrid cell DNA panel and FISH to localize the TGFBR1 gene to chromosome 9q33-q34. By FISH, Pasche et al. (1998) localized the gene to chromosome 9q22. Kuan and Kono (1998) mapped the Tgfbr1 gene to mouse chromosome 4.
Wang et al. (1994) reported that the type I receptor may be a natural ligand for immunophilin FKBP12 (186945).
The membrane-bound protein encoded by TGFBR1 binds TGF-beta and forms a heterodimeric complex with the TGF-beta II receptor (Franzen et al., 1993; Johnson et al., 1995). Ligand binding by TGF-beta I receptors is dependent on coexpression with type II receptors. Type II receptors alone can bind ligand, but require association with type I receptors for activation of their kinase (signaling) function.
TGFB stimulation leads to phosphorylation and activation of SMAD2 (601366) and SMAD3 (603109), which form complexes with SMAD4 (600993) 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.
Barrios-Rodiles et al. (2005) developed LUMIER (luminescence-based mammalian interactome mapping), an automated high-throughput technology, to map protein-protein interaction networks systematically in mammalian cells and applied it to the TGFB pathway. Analysis using self-organizing maps and k-means clustering identified links of the TGF-beta pathway to the p21-activated kinase (PAK; see 602590) network, to the polarity complex, and to occludin (602876), a structural component of tight junctions. Barrios-Rodiles et al. (2005) showed the occludin regulates TGFBR1 localization for efficient TGF-beta-dependent dissolution of tight junctions during epithelial-mesenchymal transitions.
Studying a Caucasian-dominated population in the U.S., Valle et al. (2008) showed that germline allele-specific expression (ASE) of the TGFBR1 gene is a quantitative trait that occurs in 10 to 20% of CRC patients and 1 to 3% of controls. ASE results in a reduced expression of the gene, is dominantly inherited, segregates in families, and occurs in sporadic CRC cases. Although subtle, the reduction in constitutive TGFBR1 expression alters SMAD-mediated TGF-beta signaling. Two major TGFBR1 haplotypes are predominant among ASE cases, which suggested ancestral mutations, but causative germline changes were not identified. Conservative estimates suggested that ASE confers a substantially increased risk of CRC (odds ratio, 8.7; 95% confidence interval, 2.6 to 29.1), but these estimates required confirmation and were predicted to show ethnic differences.
Loeys-Dietz Syndrome
Loeys et al. (2005) described 10 families with an aortic aneurysm syndrome characterized by hypertelorism, bifid uvula and/or cleft palate, and generalized arterial tortuosity with ascending aortic aneurysm and dissection (see LDS1, 609192). This syndrome showed autosomal dominant inheritance and variable clinical expression. Other findings in multiple systems included craniosynostosis, structural brain abnormalities such as type I Chiari malformation (118420), mental retardation, congenital heart disease (patent ductus arteriosus, atrial septal defect), and aneurysms with dissection throughout the arterial tree. Heterozygous mutations were found in the TGFBR1 gene in 4 of the 10 families and in the TGFBR2 gene (190182) in 6. Tissues derived from affected individuals showed increased expression of both collagen (see 120150) and connective tissue growth factor (CTGF; 121009), as well as nuclear enrichment of phosphorylated SMAD2, indicative of increased TGF-beta signaling.
Loeys et al. (2006) undertook the clinical and molecular characterization of the families of 40 probands presenting with typical manifestations of Loeys-Dietz syndrome (LDS1). In view of the phenotypic overlap between this syndrome and vascular Ehlers-Danlos syndrome (EDS; 130050), they screened an additional cohort of 40 patients who had been diagnosed provisionally with vascular EDS but lacked the characteristic abnormalities of type III collagen (120180). Of these 40 probands, 4 carried a heterozygous mutation in TGFBR1 (3 of which involved codon 487; see, e.g., 190181.0004 and 190181.0007) and were classified as having Loeys-Dietz syndrome-2, a phenotypic classification denoting absence of craniofacial involvement. Overall, 13 mutations were found in TGFBR1.
Ades et al. (2006) discussed the phenotypes and genotypes of 5 individuals with conditions within the Marfan syndrome/marfanoid-craniosynostosis/marfanoid-metal retardation spectrum in light of evidence of abnormal TGF-beta signaling in the pathogenesis of Marfan-like phenotypes. In 2 unrelated patients with Furlong syndrome (see 609192) they described the same missense mutation in TGFBR1 (190181.0005). The other 3 patients had alterations of the FBN1 gene (134797). Ades et al. (2006) concluded that their findings supported the notion that perturbation of extracellular matrix homeostasis and/or remodeling caused by abnormal TGF-beta signaling is the core pathogenetic mechanism in Marfan syndrome and related entities.
In patients with phenotypes classified as type 2 Marfan syndrome, Loeys-Dietz syndrome, or thoracic aortic aneurysm with dissection (TAAD), Matyas et al. (2006) detected 3 novel mutations in the TGFBR1 gene. A heterozygous arg487-to-gln (R487Q) mutation (190181.0006) was present in a patient with TAAD; mutation of the same residue to pro (R487P; 190181.0004) had been previously reported in a family whose phenotype was identified as Loeys-Dietz syndrome.
Singh et al. (2006) searched for TGFBR1 and TGFBR2 mutations in 41 unrelated patients fulfilling the diagnostic criteria of the Ghent nosology (De Paepe et al., 1996) or with a tentative diagnosis of Marfan syndrome, in whom mutations in the FBN1 coding region were not identified. In TGFBR1, 2 mutations and 2 polymorphisms were detected. In TGFBR2, 5 mutations and 6 polymorphisms were identified. Reexamination of patients with a TGFBR1 or TGFBR2 mutation revealed extensive clinical overlap between these patients.
Susceptibility To Multiple Self-Healing Squamous Epithelioma
In affected members of 18 different families with autosomal dominant multiple self-healing squamous epithelioma (MSSE; 132800), Goudie et al. (2011) identified 11 different heterozygous mutations in the TGFBR1 gene (see, e.g., 190181.0009-190181.0012). The phenotype is characterized by the development of multiple squamous carcinoma-like locally invasive skin tumors that grow rapidly for a few weeks before showing spontaneous regression, leaving scars. The mutations identified by Goudie et al. (2011) occurred in either the extracellular ligand-binding domain (exon 2) or in the serine/threonine kinase domain (exons 4, 6, and 7), and all were predicted or demonstrated to result in loss of receptor function. Several mutation carriers were unaffected, and tumor tissue from some patients showed loss of heterozygosity for the wildtype allele. Overall, the findings were consistent with wildtype TGFBR1 acting as a tumor suppressor, until somatic deletion by a classic second hit results in carcinogenesis. Goudie et al. (2011) noted that TGFBR1 mutations causing Loeys-Dietz syndrome result in activation of the TGFB1 signaling pathway, whereas TGFBR1 mutations causing MSSE result in loss of the TGFB1 signaling pathway.
Susceptibility To Abdominal Aortic Aneurysm
For discussion of a possible association between variation in the TGFBR1 gene and susceptibility to abdominal aortic aneurysm, see AAA (100070).
Associations Pending Confirmation
For discussion of a possible association between variation near the TGFBR1 gene and age-related macular degeneration, see ARMD1 (603075).
To better define the function of TGF-beta in hematopoiesis and angiogenesis, Larsson et al. (2001) used gene targeting to inactivate the Tgfbr1 gene in mice. Mice lacking Tgfbr1 died at midgestation, exhibited severe defects in the vascular development of the yolk sac and placenta, and lacked circulating red blood cells. Analysis of yolk sac-derived hematopoietic precursors of Tgfbr1 null mice revealed normal hematopoietic potential. However, endothelial cells from these embryos showed enhanced cell proliferation, improper migratory behavior, and impaired fibronectin (135600) production in vitro. Larsson et al. (2001) noted that these endothelial defects are associated with the vascular defects seen in vivo. They concluded that Tgfbr1-dependent signaling is required for angiogenesis, but not for the development of hematopoietic progenitor cells and functional hematopoiesis.
In a family with Loeys-Dietz syndrome (LDS1; 609192), Loeys et al. (2005) found a 953T-G transversion on exon 5 of the TGFBR1 gene that resulted in a met318-to-arg (M318R) substitution in the kinase domain of the protein. The mutation occurred de novo.
In a family with Loeys-Dietz syndrome (LDS1; 609192), Loeys et al. (2005) identified an 1199A-G transition in exon 7 of the TGFBR1 gene, resulting in an asp400-to-gly (D400G) substitution in the kinase domain of the protein. The mutation occurred de novo.
In a family with Loeys-Dietz syndrome (LDS1; 609192), Loeys et al. (2005) identified a 599C-T transition in exon 4 of the TGFBR1 gene that resulted in a thr200-to-ile (T200I) substitution at the junction of the glycine-serine-rich domain and the kinase domain of the TGFBR1 protein. The mutation occurred de novo.
In a family with Loeys-Dietz syndrome (LDS1; 609192), Loeys et al. (2005) found a 1460G-C transversion in exon 9 of the TGFBR1 gene that resulted in an arg487-to-pro (R487P) amino acid substitution. The R487P mutation segregated with the disorder in a father and 2 sons.
Loeys et al. (2006) classified LDS in the family reported by Loeys et al. (2005) as LDS1 on the basis of craniofacial findings, but found the same mutation in another patient with LDS classified as LDS2 (lacking typical craniofacial findings). Other missense mutations involving the same codon, R487Q (190181.0007) and R487W (190181.0007), have been identified.
In 2 patients judged to have Furlong syndrome (see LDS1, 609192), Ades et al. (2006) found an identical heterozygous missense mutation, ser241 to leu (S241L), in the TGFBR1 gene. The mutation, which arose from a C-to-T transition at nucleotide position 722, alters a highly conserved nonpolar serine in the serine-threonine kinase domain to a polar leucine residue.
In a 43-year-old patient with thoracic aortic aneurysm and dissection (see 609192), Matyas et al. (2006) found a de novo heterozygous 1460G-A transition in exon 9 of the TGFBR1 gene that caused an arg487-to-gln substitution in the protein (R487Q). Mutation at this codon had been found previously (190181.0004). The mutation occurred in the kinase domain of the protein and was predicted to affect protein function.
In a woman with Loeys-Dietz syndrome without typical craniofacial findings (LDS1; 609192), Loeys et al. (2006) found an arg487-to-trp (R487W) missense mutation in the TGFBR1 gene. The patient had aortic root aneurysm with dissection, other arterial aneurysm, arterial tortuosity, vascular rupture during pregnancy, uterine hemorrhage, bowel rupture, inguinal hernia, velvety skin, skin hyperextensibility, atrophic scars, and joint laxity. Another missense mutation at the same codon had been described (R487P; 190181.0004).
In 11 affected members of a 4-generation family with thoracic aortic aneurysm as well as aneurysms and dissections of other arteries, originally reported by Nicod et al. (1989), Tran-Fadulu et al. (2009) identified heterozygosity for the R487W mutation in the TGFBR1 gene. Imaging of the cerebrovascular circulation in 2 affected family members showed tortuous vessels and fusiform dilation of the basilar artery. Tran-Fadulu et al. (2009) stated that examination of 6 family members revealed no features of Loeys-Dietz syndrome type 1; specifically, none had bifid uvula, craniosynostosis, hypertelorism, or translucent skin.
In a 45-year-old Italian man with Loeys-Dietz syndrome (LDS1; 609192), Drera et al. (2008) identified a heterozygous 521G-T transversion in exon 3 of the TGFBR1 gene, resulting in a gly174-to-val (G174V) substitution in the intracellular region of the receptor. The mutation was not identified in 200 chromosomes from Italian controls nor in the patient's unaffected daughter. The patient had a prominent and narrow nose, thin lips, bifid uvula and cleft palate, hypermobility of small joints, and soft skin. He also had a history of dissection of both internal iliac arteries and the right femoral artery. There was no aortic root dilatation or tortuosity of the great vessels. The patient had been classified phenotypically as type 2.
In 2 symptomatic members of a Scottish family with autosomal dominant multiple self-healing squamous epithelioma (MSSE; 132800), Goudie et al. (2011) identified a heterozygous 134A-G transition in exon 2 of the TGFBR1 gene, resulting in an asn45-to-ser (N45S) substitution in the extracellular ligand-binding domain. One additional asymptomatic family member also carried the mutation, which was not found in 80 Scottish controls.
In affected individuals from 7 Scottish families with autosomal dominant multiple self-healing squamous epithelioma (MSSE; 132800), previously reported by Ferguson-Smith et al., 1971 and Goudie et al., 1993, Goudie et al. (2011) identified a heterozygous 154G-C transversion in exon 2 of the TGFBR1 gene, resulting in a gly52-to-arg (G52R) substitution in the extracellular ligand-binding domain. Asymptomatic family members in several families also carried the mutation, which was not found in 80 Scottish controls. Studies of tumor tissue from an affected individual showed that the mutant protein was expressed and localized to the plasma membrane, but there was some loss of heterozygosity for the wildtype allele. SMAD reporter assay showed that the mutant G52R receptor protein gave lower activation than the wildtype protein in response to TGFB1 stimulation, consistent with a loss of function. Overall, the findings were consistent with wildtype TGFBR1 acting as a tumor suppressor, until somatic deletion by a classic second hit results in carcinogenesis.
In 2 affected individuals from an English family with autosomal dominant multiple self-healing squamous epithelioma (MSSE; 132800), Goudie et al. (2011) identified a heterozygous A-to-C transversion (806-2A-C) in intron 4 of the TGFBR1 gene, resulting in a splice site mutation in a region containing the serine/threonine kinase domain. The mutation was predicted to result in loss of receptor signaling. The mutation was not found in 80 Scottish controls. Tumor tissue from an affected individual showed loss of heterozygosity for the wildtype allele.
In 2 affected individuals from an English family with autosomal dominant multiple self-healing squamous epithelioma (MSSE; 132800), Goudie et al. (2011) identified a heterozygous 1240C-T transition in exon 7 of the TGFBR1 gene, resulting in an arg414-to-ter (R414X) substitution in the serine/threonine kinase domain. The mutation resulted in nonsense-mediated mRNA decay, causing a loss of receptor signaling. The mutation was not found in 80 Scottish controls.
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