Alternative titles; symbols
HGNC Approved Gene Symbol: TBX4
SNOMEDCT: 720752007, 726735000;
Cytogenetic location: 17q23.2 Genomic coordinates (GRCh38): 17:61,452,422-61,485,110 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q23.2 | Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome | 601360 | Autosomal recessive | 3 |
| Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension | 147891 | Autosomal dominant | 3 |
A novel gene family of putative transcription regulators sharing a conserved homology domain with the classic mouse gene 'Brachyury' (T) was discovered by Bollag et al. (1994) and named the T-box family. Three genes, TBX1 (602054), TBX2 (600747), and TBX3 (601621), were originally described and found to be expressed at different stages of embryonic development. Later, 2 additional genes were discovered, TBX4 and TBX5 (601620) (Agulnik et al., 1996).
By screening a genomic sequence database and analysis of an EST derived from a testis cDNA library, Yi et al. (2000) obtained a cDNA encoding TBX4. The deduced protein contains 545 amino acids. Mouse and human TBX4 share more than 95% amino acid similarity overall, including 100% identity within the T-box region.
Yi et al. (2000) determined that the TBX4 gene contains at least 8 exons and spans about 50 kb.
In the mouse, Tbx4 and Tbx5 map in close linkage with Tbx2 and Tbx3, respectively (Agulnik et al., 1996). TBX2 maps to chromosome 17 in the human and chromosome 11 in the mouse; presumably, a human TBX4 homolog maps to chromosome 17 also. TBX3 and TBX5 both map to human chromosome 12 and mouse chromosome 5. Considering the close evolutionary relatedness of these 2 pairs of genes, a model of tandem duplication followed by clustered dispersion was proposed by Agulnik et al. (1996) to account for the observed arrangement. Ruvinsky and Silver (1997) stated that, if such a dispersion took place, it would be expected that other genes linked to the original cluster would be duplicated as well, and that one might find extended regions containing paralogous genes on mouse chromosomes 5 and 11. Ruvinsky and Silver (1997) found 5 pairs of related genes in the mouse, in addition to the T-box clusters, that demonstrated a genomic distribution pattern consistent with the proposed en masse duplication event. The human homologs included NOS1 (163731) on chromosome 12 and NOS2A (163730) on chromosome 17; and HNF1A (142410) on chromosome 12 and HNF1B (189907) on chromosome 17. Using data obtained from linked paralogous genes, Ruvinsky and Silver (1997) showed that the T-box cluster duplication occurred before the divergence between bony fish and tetrapods around 400 million years ago.
By genomic sequence analysis, Yi et al. (2000) mapped the TBX4 gene centromeric to TBX2 on chromosome 17q21-q22.
Lin et al. (2016) found that TBX4, a regulator of hindlimb development, is not found in the tiger tail seahorse (Hippocampus comes) genome. Knockout of tbx4 in zebrafish showed a 'pelvic fin-loss' phenotype similar to that of seahorses.
Ischiocoxopodopatellar Syndrome with or without Pulmonary Arterial Hypertension
By haplotype analysis, Bongers et al. (2004) identified a critical region of 5.6 cM for ischiocoxopodopatellar syndrome (ICPPS; 147891), also known as small patella syndrome, on 17q22. Putative loss-of-function mutations were found in the TBX4 gene in 6 families. TBX4 encodes a transcription factor that plays a critical role in lower limb development in chickens and mice. The identification of heterozygous TBX4 mutations in patients with small patella syndrome, together with the similar skeletal phenotype of animals lacking Tbx4, established the importance of the TBX4 gene in the developmental pathways of the lower limbs and the pelvis in humans.
In a study of 20 consecutive patients with childhood-onset pulmonary arterial hypertension (PAH; see 178600), Kerstjens-Frederikse et al. (2013) found that 3 patients had mutations (2 frameshift and 1 missense) in the TBX4 gene (see, e.g., 601719.0004) and 3 others had TBX4-containing deletions. All 3 mutations were inherited. In the 5 patients still alive, and in the 2 carrier parents tested, skeletal malformations characteristic of ICPPS were found. However, TBX4 mutations were identified in only 2% (1/49) of patients with adult-onset PAH versus 18% (9/49) with BMPR2 (600799) mutations.
Levy et al. (2016) studied a cohort of 40 patients with idiopathic or familial pulmonary hypertension and identified heterozygous TBX4 mutations in 3 patients (7.5%). All of the mutations were inherited from parents with ICPPS and without PAH.
Navas et al. (2016) studied 165 Spanish patients with idiopathic or familial pulmonary arterial hypertension and identified 3 TBX4 variants in the cohort. Two of the variants were labeled as variants of unknown significance, but one, a 3-bp insertion (glu) after codon 104, was predicted to be pathogenic and was not found in ExAC. In family members of the proband who carried the mutation, one had PAH and one did not. Individuals with variants in TBX4 had longer survival than those with mutations in the BMPR2 gene.
Galambos et al. (2019) reported 13 patients with ICPPS who had heterozygous frameshift, nonsense, or missense mutations in the TBX4 gene; 7 of the mutations were inherited, 2 occurred de novo, and for 4 the inheritance was unknown (see, e.g., 601719.0006-601719.0009).
Posterior Amelia with Pelvic and Pulmonary Hypoplasia Syndrome
In 2 unrelated consanguineous Iranian families in which the parents had ICPPS and 4 fetuses exhibited absent lower limbs and pelvic and pulmonary hypoplasia (PAPPAS; 601360), Kariminejad et al. (2019) identified mutations in the TBX4 gene. In the first family, a nonsense mutation (Y113X; 601719.0010) was present in homozygosity in an affected fetus and in heterozygosity in the second-cousin parents, whereas 2 healthy sons did not carry the mutation. In the second family, a missense mutation (Y127N) was present in heterozygosity in the first-cousin parents and was not found in a healthy child; DNA was unavailable from the fetus with PAPPAS.
In an Indian family in which 3 fetuses had PAPPAS, Ranganath et al. (2020) identified homozygosity for a nonsense mutation in the TBX4 gene (W134X; 601719.0011) in an affected fetus. The consanguineous parents were heterozygous for the mutation; both exhibited features consistent with mild ICPPS.
Associations Pending Confirmation
Suhrie et al. (2019) reported 2 neonates with pulmonary hypoplasia (265430). Infant A carried a de novo frameshift in the TBX4 gene and a missense mutation in the ABCA3 gene (c.863G-A, R288K). The missense mutation is present in all ethnic groups except East Asians in gnomAD at an overall frequency of 0.6% (Hamosh, 2019). Infant B had a 2.2-Mb deletion on chromosome 17q23.1-q23.2 (see 613355) that included the TBX4 gene and the identical ABCA3 variant.
Karolak et al. (2019) studied a cohort of 26 deceased patients who had clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia in 14 patients, congenital alveolar dysplasia in 2, and other lethal lung hypoplasias in 10. The authors identified rare heterozygous copy number variants or deletions involving TBX4 (8 and 2, respectively) or FGF10 (602115) (2 and 2, respectively) in 16 (61%) of the 26 patients. Individuals with lung hypoplasia also harbored at least one noncoding single nucleotide variant (SNV) in the predicted lung-specific enhancer region. One patient (P025) was previously reported by Szafranski et al. (2016) to have a glu86-to-gln (E86Q; 601719.0005) mutation in the TBX4 gene. This variant was not found in the gnomAD database. Another infant (P022) carried a different change (E86K) at the same codon in TBX4. No functional studies were reported.
Pitx1 (602149) and Tbx4 encode transcription factors that are expressed throughout the developing hindlimb, but not in forelimb buds. Logan and Tabin (1999) injected a retroviral vector carrying Pitx1 into the wing field of chicken embryos. Misexpression of Pitx1 in the chick wing bud induced distal expression of Tbx4, as well as HoxC10 and HoxC11, which are normally restricted to hindlimb expression domains. Wing buds in which Pitx1 was misexpressed developed into limbs with some morphologic characteristics of hindlimbs: the flexure was altered to that normally observed in legs, the digits were more toe-like in the relative size and shape, and the muscle pattern was transformed to that of a leg. Expression of Tbx5, normally expressed only in the forelimb, was not altered by Pitx1 misexpression.
By gene targeting and transgenic methods, Minguillon et al. (2005) examined the ability of Tbx4 and Pitx1 to rescue the no-forelimb phenotype of mutant mice with Tbx5 knockout restricted to limbs. Tbx4 could replace Tbx5 and rescue limb outgrowth, but Pitx1 could not. In contrast to previous chick misexpression studies, Tbx4-rescued limbs had a forelimb-like phenotype, suggesting that Tbx4 alone does not dictate hindlimb morphology and that forelimb characteristics can develop in the absence of Tbx5. To determine the role of Pitx1 in defining hindlimb characteristics, Minguillon et al. (2005) introduced forelimb-targeted Pitx1 into mice expressing endogenous Tbx5 and into mutant mice rescued by Tbx4. In both cases, forelimb-targeted Pitx1 expression caused a partial forelimb-to-hindlimb transformation, indicating that Pitx1 has a role in directing hindlimb morphology.
Kariminejad et al. (2019) injected tbx4 gRNA1 with Cas9 protein unilaterally in 1 ventral blastomere of 4-cell-stage Xenopus tropicalis embryos. Across 2 experimental repeats, 10% and 6.66% of the resulting F0 mosaic tadpoles manifested striking unilateral hindlimb defects, but no forelimb anomalies. The most strongly affected animals had severely underdeveloped hindlimbs with a reduced number of toes that still carried claws, and the hindlimbs were completely covered with pigmented skin (normally present only on the dorsum), suggesting that Tbx4 inactivation may result in dorsalization of the affected hindlimb. The less severely affected animals presented with smaller hindlimbs that were not used for swimming, with normal forelimbs on the injected side. Alizarin red and alcian blue staining revealed a shorter femur and dislocated joints at both the hip and the knee.
In a Dutch family with ischiocoxopodopatellar syndrome (ICPPS; 147891) reported by Bongers et al. (2001), Bongers et al. (2004) found that affected members had a heterozygous 743G-T transversion in exon 6 of the TBX4 gene, predicted to cause a gly248-to-val (G248V) amino acid change.
In a Dutch family with ischiocoxopodopatellar syndrome (ICPPS; 147891) reported by Bongers et al. (2001), Bongers et al. (2004) identified a heterozygous nonsense mutation, gln62-to-stop (Q62X), resulting from a 184C-T transition in exon 1 of the TBX4 gene.
In a Dutch family with ischiocoxopodopatellar syndrome (ICPPS; 147891), Bongers et al. (2004) identified a heterozygous gln531-to-arg (Q531R) mutation in exon 8 of the TBX4 gene that arose from a 1592A-G transition.
In a study of 20 consecutive patients with childhood-onset pulmonary arterial hypertension, Kerstjens-Frederikse et al. (2013) found 1 female with a heterozygous 1-bp insertion (c.355_356insA) in exon 3 of the TBX4 gene, resulting in a frameshift and a premature termination codon (Ile119AsnfsTer6). The mutation, which was not found in 1000 control chromosomes, was inherited from her mother. Examination of the proband and her mother demonstrated that both had characteristic features of ischiocoxopodopatellar syndrome (ICPPS; 147891). The mother did not have pulmonary arterial hypertension.
This variant is classified as a variant of unknown significant because its contribution to pulmonary hypoplasia (see 265430) has not been confirmed.
Szafranski et al. (2016) and Karolak et al. (2019) each reported the same infant with neonatal lethal pulmonary hypoplasia who had a de novo c.256G-C transversion (c.256G-C, NM_018488.3) in the TBX4 gene, resulting in a glu86-to-gln (E86Q) substitution. The variant was not found in the gnomAD database. No functional studies were reported.
In a female infant (patient 7) with ischiocoxopodopatellar syndrome with pulmonary arterial hypertension (ICPPS; 147891), Galambos et al. (2019) identified a de novo heterozygous 1-bp deletion (c.251delG, NM_001321120.1) in the TBX4 gene, resulting in a gly84-to-ala (G84A) substitution, followed by a frameshift and a premature termination codon 4 amino acids downstream. The mutation was not found in the ExAC database. The patient presented with hypoxia and dyspnea at 6 weeks of age. She also had transient patent ductus arteriosus (PDA), failure to thrive, and developmental delay. She died of a pulmonary hypertension crisis during surgery at age 8 months for a Meckel diverticulum.
In an 11-year-old girl (patient 12) with ischiocoxopodopatellar syndrome (ICPPS; 147891), Galambos et al. (2019) identified a heterozygous c.1054C-T transition (c.1054C-T, NM_001321120.1) in the TBX4 gene, resulting in an arg352-to-ter (R352X) substitution. The mutation was inherited from her mother, who also had small patella syndrome. The variant was not present in the ExAC database. The patient presented with hypoxia and interstitial lung disease at age 2.5 years and eventually required heart-lung transplantation. The patient also had an atrial septal defect (ASD). She did not have developmental deficits.
In a 10-year-old girl (patient 15) with ischiocoxopodopatellar syndrome without pulmonary arterial hypertension (ICPPS; 147891), Galambos et al. (2019) identified a heterozygous splice site mutation (c.291-1G-C, NM_001321120.1) in the TBX4 gene. The patient presented with respiratory distress and pneumothorax at 5 months of age due to respiratory syncytial virus infection and then had persistent childhood interstitial lung disease. The mutation was inherited from her mother, who had small patella syndrome with interstitial lung disease but without pulmonary hypertension. The variant was not present in the ExAC database. The proband also had a foot anomaly and a mandibular angioma, but no developmental deficits.
In a 9-year-old boy (patient 18) with ischiocoxopodopatellar syndrome with pulmonary arterial hypertension (ICPPS; 147891), Galambos et al. (2019) identified a c.557T-G transversion (c.557T-G, NM_001321120.1) in the TBX4 gene, resulting in a leu186-to-arg (L186R) substitution. The variant was not present in the ExAC database. The proband presented at age 7 years with interstitial lung disease requiring inhaled nitric oxide and a 92-day hospitalization. He had moderate pulmonary hypertension. He also had pelvic, vertebral, and foot anomalies, ASD, PDA, short stature, long philtrum, and hypertelorism, as well as moderate developmental delay and hypotonia. He had 2 sibs with small patella syndrome who carried the same variant. There was no further description of his sibs.
In a consanguineous Iranian family (family 1) in which 3 fetuses had posterior amelia with pelvic and pulmonary hypoplasia syndrome (PAPPAS; 601360) and the parents had ischiocoxopodopatellar syndrome (ICPPS; 147891), Kariminejad et al. (2019) identified a c.339T-A transversion (c.339T-A, NM_001321120.1) in exon 4 of the TBX4 gene, resulting in a tyr113-to-ter (Y113X) substitution. The mutation was present in homozygosity in an affected fetus (F1-IV:5) and in heterozygosity in the second-cousin parents, whereas 2 healthy sons did not carry the mutation. RT-PCR analysis of cDNA from forelimb tissue from F1-IV:5 showed no detectable expression of endogenous TBX4 transcript.
In a consanguineous Indian family in which 3 fetuses had posterior amelia with pelvic and pulmonary hypoplasia syndrome (PAPPAS; 601360) and the parents had ischiocoxopodopatellar syndrome (ICPPS; 147891), Ranganath et al. (2020) identified a c.402G-A transition (c.402G-A, NM_018488.2) in the TBX4 gene, resulting in a trp134-to-ter (W134X) substitution. The mutation, which was detected in homozygosity in an affected fetus and in heterozygosity in the consanguineous parents, was not found in 700 exomes in an in-house database from the Indian population, or in the 1000 Genomes Project, ExAC, or gnomAD databases.
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