TRANSFORMING GROWTH FACTOR, BETA-3; TGFB3

HGNC Approved Gene Symbol: TGFB3

Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38): 14:75,958,096-75,983,010 (from NCBI)

▼ Cloning and Expression
Beta-type transforming growth factors are polypeptides that act hormonally to control the proliferation and differentiation of multiple cell types. A cDNA clone for a third form of TGFB was isolated by ten Dijke et al. (1988). The C-terminal 112 amino acids of TGF-beta-3 share approximately 80% sequence identity with beta-1 (190180) and beta-2 (190220).

Moren et al. (1992) isolated full-length cDNAs for TGFB3 from a human placenta cDNA library. The coding region encoded a protein of 849 amino acids with a single transmembrane domain and a short stretch of the intracellular domain.

▼ Mapping
By Southern analysis of DNA prepared from somatic cell hybrids and by in situ hybridization, ten Dijke et al. (1988) assigned the TGFB3 gene to chromosome 14q23-q24. Barton et al. (1988) likewise assigned the TGFB3 gene to chromosome 14 and regionalized it to 14q24 by Southern blot analysis of hybrid cell DNAs and by in situ hybridization.

The mouse Tgfb3 gene was mapped to chromosome 12 (Barton et al., 1988; Dickinson et al., 1990).

▼ Gene Function
Graycar et al. (1989) purified to apparent homogeneity human TGFB3 and evaluated its activities in comparison to TGFB1 and TGFB2.

Lee and Nowak (2001) compared expression of the TGFB isoforms in normal myometrium and benign leiomyoma tumors of the uterus (150699) and examined the effects of TGFBs on cell proliferation and collagen production by these cells in vitro. Northern blot analysis showed that the levels of TGFB1 mRNA were similar between leiomyoma and myometrium, whereas leiomyoma showed 5-fold higher levels of expression of TGFB3 mRNA than autologous myometrium. Expression of TGFB3 protein detected by immunohistochemistry was much more intense in leiomyoma tissues than in corresponding myometrium. The authors concluded that their results support the hypothesis that alterations in the TGFB system produce loss of sensitivity to the antiproliferative effects of TGFB, and increased expression of TGFB3 may contribute to the growth of these tumors.

Epithelial mesenchymal transformation (EMT) of the medial edge epithelial seam creates palatal confluence. Nawshad and Hay (2003) showed that Tgfb3 brought about palatal seam EMT in mice by stimulating expression of Lef1 (153245) in medial edge epithelial cells. Tgfb3 activated Lef1 in the absence of beta-catenin (CTNNB1; 116806) via nuclear phospho-Smad2 (601366) and Smad4 (600993).

Using transfected 293 EBNA cells, Venza et al. (2011) showed that MSX1 (142983) and TGFB3 are direct targets of the forkhead transcription factor FOXE1 (602617). They found that mutations in the FOXE1 forkhead domain, which are linked to Bamforth-Lazarus syndrome (241850), reduced or eliminated FOXE1-dependent MSX1 and TGFB3 upregulation.

▼ Molecular Genetics
Arrhythmogenic Right Ventricular Dysplasia 1

Beffagna et al. (2005) screened 38 members of a 4-generation Italian family with arrhythmogenic right ventricular dysplasia-1 (ARVD1; 107970), previously reported by Rampazzo et al. (2003), and identified a mutation (190230.0001) in the 5-prime UTR of the TGFB3 gene. Subsequent screening of 30 unrelated individuals with ARVD1 led to the identification of an additional mutation (190230.0002) in the 3-prime UTR of the TGFB3 gene in 1 patient. In transfection studies, both mutations showed significantly higher luciferase reporter activity (about 2.5-fold, p less than 0.01) compared to wildtype.

In a case-control study of 711 Japanese individuals with ossification of the posterior longitudinal ligament of the spine (OPLL; 602475) and 896 controls, Horikoshi et al. (2006) found an association between an intronic SNP in the TGFB3 gene (rs2268624) and OPLL.

Loeys-Dietz Syndrome 5

In a 9-year-old girl with low muscle mass, growth retardation, and distal arthrogryposis, who also exhibited features of Loeys-Dietz syndrome (LDS5; 615582) as well as Marfan (154700) and Beals (121050) syndromes, but who did not meet the diagnostic criteria for those syndromes, Rienhoff et al. (2013) analyzed 6 genes known to be associated with those disorders, including TGFB2 (190220), TGFBR1 (190181), TGFBR2 (190182), SMAD3 (603109), FBN1 (134797), and FBN2 (612570), but found no mutations. Exome sequencing revealed a de novo missense mutation in the TGFB3 gene (C409Y; 190230.0003), encoding a nonfunctional TGFB3 ligand.

In a 10.5-year-old girl with low muscle mass, marfanoid features, and bifid uvula, who was negative for mutation in FBN1, TGFBR1, TGFBR2, TGFB2, and SMAD3, Matyas et al. (2014) identified heterozygosity for a de novo missense mutation in the TGFB3 gene (R300Q; 190230.0004).

In a large Dutch pedigree with syndromic aortic aneurysm, negative for mutation in 15 known thoracic aortic aneurysm/dissection (TAAD)-associated genes, Bertoli-Avella et al. (2015) identified heterozygosity for a splice site mutation in the TGFB3 gene (190230.0005). The mutation, which segregated with disease in the family, was not found in variant databases. Analysis of TGFB3 in an additional 470 probands with syndromic or nonsyndromic TAAD, the majority of whom had been screened for mutation in all known TAAD genes, revealed TGFB3 mutations in 10 probands, including 4 different missense mutations, 2 single-base deletions, and 1 nonsense mutation (see, e.g., 190230.0006-190230.0008). The authors noted that although studies in a Xenopus model led Rienhoff et al. (2013) to hypothesize that the mutated C409Y allele results in a nonfunctional protein, Bertoli-Avella et al. (2015) observed increased TGFB signaling in aortic tissue from a patient with a different missense mutation (D263H; 190230.0008).

▼ Animal Model
Proetzel et al. (1995) produced Tgfb3-null mice in which exon 6 of the Tgfb3 gene was replaced by the neomycin-resistance gene. Whereas heterozygotes had no apparent phenotypic change, homozygotes had an incompletely penetrant failure of the palatal shelves to fuse, leading to cleft palate. The defect appeared to result from impaired adhesion of the apposing medial edge epithelial of the palatal shelves and subsequent elimination of the midline epithelial seam. No craniofacial abnormalities were observed. Defective palatogenesis was also found in homozygous Tgfb3-null mutant mice by Kaartinen et al. (1995) who also found a consistent delay in pulmonary development. They suggested that the study demonstrates an essential function for TGF-beta-3 in normal palate and lung morphogenesis and implicates this cytokine in epithelial-mesenchymal interaction.

▼ ALLELIC VARIANTS ( 8 Selected Examples):

.0001 ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA 1
TGFB3, -36G-A, 5-PRIME UTR
In 9 affected and 3 unaffected members of a 4-generation Italian family with arrhythmogenic right ventricular dysplasia-1 (ARVD1; 107970) previously reported by Rampazzo et al. (2003), Beffagna et al. (2005) identified a G-to-A transition at cDNA position -36 in the 5-prime UTR of the TGFB3 gene (c.-36G-A, NM_003239). In transfection studies, the mutant construct showed significantly higher luciferase reporter activity (about 2.5-fold, p less than 0.01) compared to wildtype constructs. All clinically affected members of the family had the mutation; Beffagna et al. (2005) stated that detection of the mutation in 3 apparently healthy individuals was consistent with reduced penetrance.

.0002 ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA 1
TGFB3, 1723C-T, 3-PRIME UTR
In a young man with arrhythmogenic right ventricular dysplasia-1 (ARVD1; 107970), Beffagna et al. (2005) identified a C-to-T transition at cDNA position 1723 in the 3-prime UTR of the TGFB3 gene (c.1723C-T, NM_003239). In transfection studies, the mutant construct showed significantly higher luciferase reporter activity (about 2.5-fold, p less than 0.01) compared to wildtype constructs. The patient had a brother who died suddenly at the age of 16 and was found to have ARVD at autopsy.

.0003 LOEYS-DIETZ SYNDROME 5
TGFB3, CYS409TYR
In a 9-year-old girl with low muscle mass, growth retardation, and distal arthrogryposis, who also exhibited blue sclerae, bifid uvula, and hyperextensibility of the large joints (LDS5; 615582), Rienhoff et al. (2013) identified heterozygosity for a de novo c.1226G-A transition in the TGFB3 gene, resulting in a cys409-to-tyr (C409Y) substitution. The mutation was not found in the dbSNP (build 130), Exome Variant Server, or 1000 Genomes Project databases. Functional analysis in transfected HEK293T cells showed that wildtype TGFB3 generated a transcriptional signal whereas the C409Y mutant did not. In Xenopus embryos, a 1:1 ratio of mutant to wildtype TGFB3 RNA diminished the SMAD2 (601366) and ERK1 (601795)/2 (176948) signals to approximately 40% and 60% of that generated by wildtype TGFB3 RNA alone.

.0004 LOEYS-DIETZ SYNDROME 5
TGFB3, ARG300GLN
In a 10.5-year-old girl with Loeys-Dietz syndrome-5 (LDS5; 615582), Matyas et al. (2014) identified heterozygosity for a de novo c.899G-A transition in the TGFB3 gene, resulting in an arg300-to-gln (R300Q) substitution at the last residue of the potential furin (136950) cleavage site in the C-terminal end of the LAP domain.

.0005 LOEYS-DIETZ SYNDROME 5
TGFB3, IVS4DS, T-C, +2
In 4 affected individuals over 3 generations of a large Dutch family with Loeys-Dietz syndrome-5 (LDS5; 615582), Bertoli-Avella et al. (2015) identified heterozygosity for a c.754+2T-C transition (c.754+2T-C, NM_003239.2) in intron 4 of the TGFB3 gene. The mutation, which segregated with disease in the family, was not found in the Exome Variant Server, Genome of the Netherlands, or 1000 Genomes Project databases. Analysis of cDNA from 2 affected individuals confirmed that the mutation causes skipping of exon 4, resulting in an in-frame deletion of 36 amino acids (Glu216_Lys251del) involving a central beta strand and subsequent surface loop in the LAP domain.

.0006 LOEYS-DIETZ SYNDROME 5
TGFB3, ARG300TRP
In affected members of 4 unrelated families with Loeys-Dietz syndrome-5 (LDS5; 615582), Bertoli-Avella et al. (2015) identified heterozygosity for a c.898C-T transition (c.898C-T, NM_003239.2) in exon 5 of the TGFB3 gene, resulting in an arg300-to-trp (R300W) substitution at the highly conserved last residue of the RKKR minimal recognition motif of the furin (136950) or related protease cleavage site. The mutation, which segregated with disease in each of the families, was not found in the Exome Variant Server, 1000 Genomes Project, or Genome of the Netherlands databases. The youngest patient to carry this mutation was a 3-year-old Japanese girl who had a 19.5-mm aortic root aneurysm and atrial and ventricular septal defects, as well as other features of LDS, including hypertelorism, bifid uvula, and osteoarthritis.

.0007 LOEYS-DIETZ SYNDROME 5
TGFB3, 1-BP DEL, 704A
In a Japanese mother and son with Loeys-Dietz syndrome-5 (LDS5; 615582), Bertoli-Avella et al. (2015) identified heterozygosity for a 1-bp deletion (c.704delA, NM_003239.2) in exon 4 of the TGFB3 gene, causing a frameshift predicted to result in a premature termination codon (Asn235MetfsTer11). The mutation was not found in an unaffected daughter or in the Exome Variant Server, 1000 Genomes Project, or Genome of the Netherlands databases. The 67-year-old mother and 43-year-old son were both diagnosed with thoracic aortic aneurysm with type A dissections at age 59 and 40 years of age, respectively, and both were tall; in addition, the mother had arachnodactyly, inguinal hernia, and myopia, whereas the son exhibited kyphoscoliosis and pectus deformity, retrognathia, and flat occiput. The maternal grandfather had died of thoracic aortic aneurysm dissection at age 80 years.

.0008 LOEYS-DIETZ SYNDROME 5
TGFB3, ASP263HIS
In a 31-year-old man who had thoracic aortic aneurysm dissection (TAAD) at age 30 with a 70-mm aortic root and who also exhibited dolichocephaly, high-arched palate, severe retrognathia, delayed puberty, and short stature (LDS5; 615582), Bertoli-Avella et al. (2015) identified heterozygosity for a c.787G-C transversion (c.787G-C, NM_003239.2) in exon 5 of the TGFB3 gene, resulting in an asp263-to-his (D263H) substitution at a highly conserved residue in the RGD motif of the LAP domain. The mutation was present in his 70-year-old maternal aunt, who had a 38-mm aortic sinus diameter and mild mitral insufficiency; it was also found in his 64-year-old mother, who had mild mitral insufficiency but an aortic sinus diameter of only 34 mm, and in his asymptomatic 34-year-old brother, who had an aortic sinus diameter of 32 mm. Microscopic examination of the proband's dissected aortic wall showed elastic fiber fragmentation with higher collagen and proteoglycan deposition. Immunohistochemical analysis of aortic tissue showed paradoxically enhanced TGF-beta (TGFB1; 190180) signaling, as shown by increased levels of SMAD2 (601366) and ERK (see 601795) as well as elevated TGFB1 mRNA.