Other entities represented in this entry:
HGNC Approved Gene Symbol: LTBP4
SNOMEDCT: 784349004;
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38) : 19:40,593,166-40,629,820 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | Cutis laxa, autosomal recessive, type IC | 613177 | Autosomal recessive | 3 |
Transforming growth factor-beta, or TGFB (see TGFB1; 190180), remains biologically latent after secretion, blocked from activity by its N-terminal propeptide (the latency-associated peptide, or LAP). TGFB is activated by its dissociation from LAP. The latent form of TGFB is secreted in association with a latent TGFB-binding protein, or LTBP (see LTBP1; 150390), and assembled into the extracellular matrix. LTBPs are mainly composed of epidermal growth factor (EGF; 131530)-like repeats and protein domains with 8-cysteine repeats, both of which are also found in fibrillins (e.g., 134797).
See Oklu and Hesketh (2000) for a review of the LTBP gene family.
By searching an EST database for cDNAs encoding EGF-like repeat-containing proteins, Giltay et al. (1997) identified a cDNA encoding a deduced 1,587-amino acid protein, which they called LTBP4. Northern blot analysis detected strong expression of an approximately 5-kb LTBP4 transcript in heart, with slightly lower expression in skeletal muscle and pancreas, moderate expression in placenta and lung, and weak or no expression in brain, liver, and kidney.
By searching an EST database for cDNAs encoding 8-cysteine repeat-containing proteins, Saharinen et al. (1998) isolated a human heart cDNA encoding a deduced 1,511-amino acid protein, which they termed LTBP4S. The authors also obtained cDNAs encoding 3 alternatively spliced forms of LTBP4, including a partial cDNA encoding an N-terminally extended form of LTBP4S that they called LTBP4L. Northern blot analysis detected a 5.1-kb LTBP4 transcript that was strongly expressed in heart, uterus, and small intestine, and weakly expressed in placenta, lung, and skeletal muscle. In addition to these tissues, dot blot hybridization detected significant levels of LTBP4 mRNA in aorta, ovary, and adrenal gland. Immunoblot analysis of serum-free medium of fibroblast cultures detected a proteinase-sensitive LTBP4 protein of 250 kD that binds in a covalent complex with TGFB1-LAP and associates with extracellular matrix.
Su et al. (2015) found that human skin fibroblasts with loss-of-function mutations in LTBP4 have depressed intracellular TGF-beta signaling despite elevated extracellular TGF-beta activity. LTBP4 mutant or knockdown fibroblasts also had reduced abundance of protein, but not mRNA, for the TGF-beta receptors TGFBR1 (190181) and TGFBR2 (190182). Knockdown of LTBP4 in normal skin fibroblasts via antisense morpholinos also depressed phosphorylation of SMAD2 (601366) and ERK (see 601795). Coimmunoprecipitation analysis revealed that LTBP4 interacted directly with TGFBR2. Inhibitor studies showed that LTBP4 stabilized TGFBR1 and TGFBR2 against endocytosis and lysosome-mediated degradation.
By FISH, Saharinen et al. (1998) mapped the LTBP4 gene to chromosome 19q13.1-q13.2.
In 4 unrelated patients with cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities (ARCL1C; 613177), Urban et al. (2009) identified 5 homozygous or compound heterozygous mutations in the LTBP4 gene (604710.0001-604710.0005). Four of the mutations were predicted to lead to premature termination codons, and one replaced a highly conserved cysteine in a hybrid domain. Four of the 5 mutations were located in a hybrid or an 8-cysteine domain, which are known to have long-range effects on fibrillin and LTBP conformation.
Callewaert et al. (2013) analyzed the FBLN4 (604633), FBLN5 (604580), and LTBP4 genes in 12 families with type I ARCL and identified homozygous or compound heterozygous mutations in the LTBP4 gene in 9 families (see, e.g., 604710.0005-604710.0008). Homozygous mutations in FLBN5 were identified in 2 families (604580.0010 and 604580.0011, respectively). No mutations were found in the FBLN4 gene, and no mutations were detected in 1 family in which the proband had cutis laxa and bladder diverticula without obvious emphysema. Callewaert et al. (2013) noted that the FBLN5 and LTBP4 mutations caused a very similar phenotype associated with severe pulmonary emphysema in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seemed to be more severe in patients with LTBP4 mutations.
By using a gene trap strategy that selects for integrations into genes induced transiently during early mouse development, Sterner-Kock et al. (2002) disrupted the mouse homolog of the human LTBP4 gene. Mice homozygous for the disrupted allele developed severe pulmonary emphysema, cardiomyopathy, and colorectal cancer. These highly tissue-specific abnormalities were associated with profound defects in the elastic fiber structure and with a reduced deposition of TGF-beta in the extracellular space, resulting in epithelial cells with reduced levels of phosphorylated Smad2 (601366) proteins, overexpression of c-myc (190080), and uncontrolled proliferation. This phenotype supported the predicted dual role of LTBP4 as a structural component of the extracellular matrix and as a local regulator of TGF-beta tissue deposition and signaling.
Su et al. (2015) found that skin fibroblasts of mice lacking expression of Ltbp4s (Sterner-Kock et al., 2002) had reduced Tgfbr1 and Tgfbr2 levels, with concomitant reductions in Smad2 and Erk phosphorylation.
In a patient with cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities (ARCL1C; 613177), offspring of second-cousin Hispanic parents, Urban et al. (2009) identified homozygosity for a 3554delA mutation in exon 28 of the LTBP4 gene resulting in a frameshift and a truncated protein (Gln1185fsTer1211). The mutation occurred in an 8-cysteine domain.
In a patient with cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities (ARCL1C; 613177), offspring of unrelated Mexican parents, Urban et al. (2009) identified compound heterozygosity for 2 mutations in the LTBP4 gene: a 1-bp deletion (791delC) in exon 9 resulting in a frameshift and a truncated protein (Pro264fsTer300), and a 2-bp insertion/deletion mutation (2570_2571delCGinsAA) resulting in a cys857-to-ter (C857X; 604710.0003) substitution. The former mutation occurred in a hybrid domain.
For discussion of the cys857-to-ter (C857X) mutation in the LTBP4 gene that was found in compound heterozygous state in a patient with cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities (ARCL1C; 613177) by Urban et al. (2009), see 604710.0002.
In a patient with cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities (ARCL1C; 613177), offspring of first-cousin Palestinian parents, Urban et al. (2009) identified homozygosity for an 820T-G transversion in exon 9 of the LTBP4 gene resulting in a cys274-to-gly (C274G) substitution. The mutation occurred in a hybrid domain.
In a patient with cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities (ARCL1C; 613177), offspring of unrelated Hispanic parents, Urban et al. (2009) identified compound heterozygosity for 2 mutations in the LTBP4 gene: C857X (604710.0003) and a 1-bp insertion (4128insC) in exon 33 resulting in a frameshift and a truncated protein (Pro1376fsTer1403). The latter mutation occurred in an 8-cysteine domain. Neither mutation was identified in the mother and the father was not available for study.
In 2 sisters from a consanguineous family who had cutis laxa with pulmonary and gastrointestinal involvement, Callewaert et al. (2013) identified homozygosity for a 4127dupC mutation, which they stated was the same mutation previously reported by Urban et al. (2009). The mutation was present in heterozygosity in the unaffected parents. The mother had had 3 spontaneous abortions, and an older brother with generalized cutis laxa had died after a bowel rupture at 5 days of age. In addition to cutis laxa, the proband had atrial septal defect with dysplastic aortic and pulmonary valves, esophageal tortuosity, and diaphragmatic hernia, and underwent gastric perforation. Her 8-year-old sister also had bowel perforation which was surgically repaired, and underwent Nissen fundoplasty and gastrostomy tube placement for volvulus through a massive hiatal hernia; her other features included mitral valve prolapse, palpitations, and syncope. Skin fibroblasts from the proband showed residual expression of mutant LTBP4 mRNA, suggesting partial escape from nonsense-mediated decay; this was confirmed by immunoblotting analysis of conditioned media samples from mutant fibroblasts, in which LTBP4 was detectable using an antibody against the amino terminus but not with an antibody against the carboxy terminus. Double immunostaining for LTBP4 and fibrillin-1 (134797) in patient fibroblasts showed strong extracellular matrix staining and complete colocalization with fibrillin-1 microfibrils, which were abnormally thick and wavy, indicating that the truncated LTBP4 alters fibrillin-1 microfibril bundle formation and elongation. TGFB1 (190180) levels were similar in patient fibroblasts and controls.
In a 23-year-old woman with cutis laxa (ARCL1C; 613177) primarily localized to the thorax, abdomen, and thighs, Callewaert et al. (2013) identified compound heterozygosity for a 1342C-T transition in the LTBP4 gene, resulting in an arg448-to-ter (R448X) substitution in the first 8-cys domain, and a 1-bp duplication (4115dupC; 614710.0007), causing a frameshift predicted to result in a premature termination codon (Tyr1373IlefsTer2) in the third 8-cys domain. Additional features in this patient included mild pulmonary emphysema, diaphragmatic hernia, severe bladder diverticulae requiring an artificial bladder, rectal prolapse, joint hypermobility, and mild facial dysmorphism with large ears and a beaked nose. The patient had an affected sib who died at 2 years of age. Patient fibroblasts showed greatly reduced expression of mutant LTBP4 compared to controls at both the mRNA and protein levels; double immunostaining for LTBP4 and fibrillin-1 (134797) showed no extracellular LTBP4 staining and fibrillin-1 microfibrils appeared normal. Patient cells released significantly higher levels of TGFB1 (190180) than controls (p = 0.0001).
For discussion of the 1-bp duplication in the LTBP4 gene (4115dupC) that was found in compound heterozygous state in a patient with cutis laxa (ARCL1C; 613177) primarily localized to the thorax, abdomen, and thighs by Callewaert et al. (2013), see 604710.0006.
In a 13-year-old girl with mild cutis laxa associated with emphysema (ARCL1C; 613177) who died of brain abscesses, Callewaert et al. (2013) identified homozygosity for a 4129C-T transition in the LTBP4 gene, resulting in an arg1337-to-ter (R1337X) substitution in the third 8-cys domain. The patient's emphysema appeared mild on CT, but lung function tests showed severe obstructive disease with a Tiffeneau index of 41%. She had bladder diverticulae with secondary hydronephrosis, requiring ureterostomy. Other features included patent foramen ovale, tricuspid insufficiency, peripheral pulmonary artery stenosis, pulmonary hypertension, and dysmorphism consisting of prominent forehead, blepharochalasis, epicanthal folds, short nose, elongated and marked philtrum, low-set large ears, webbed neck, and low posterior hairline.
Callewaert, B., Su, C.-T., Van Damme, T., Vlummens, P., Malfait, F., Vanakker, O., Schulz, B., Mac Neal, M., Davis, E. C., Lee, J. G. H., Salhi, A., Unger, S., and 16 others. Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa. Hum. Mutat. 34: 111-121, 2013. [PubMed: 22829427] [Full Text: https://doi.org/10.1002/humu.22165]
Giltay, R., Kostka, G., Timpl, R. Sequence and expression of a novel member (LTBP-4) of the family of latent transforming growth factor-beta binding proteins. FEBS Lett. 411: 164-168, 1997. [PubMed: 9271198] [Full Text: https://doi.org/10.1016/s0014-5793(97)00685-6]
Oklu, R., Hesketh, R. The latent transforming growth factor beta binding protein (LTBP) family. Biochem. J. 352: 601-610, 2000. [PubMed: 11104663]
Saharinen, J., Taipale, J., Monni, O., Keski-Oja, J. Identification and characterization of a new latent transforming growth factor-beta-binding protein, LTBP-4. J. Biol. Chem. 273: 18459-18469, 1998. [PubMed: 9660815] [Full Text: https://doi.org/10.1074/jbc.273.29.18459]
Sterner-Kock, A., Thorey, I. S., Koli, K., Wempe, F., Otte, J., Bangsow, T., Kuhlmeier, K., Kirschner, T., Jin, S., Keski-Oja, J., von Melchner, H. Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer. Genes Dev. 16: 2264-2273, 2002. [PubMed: 12208849] [Full Text: https://doi.org/10.1101/gad.229102]
Su, C.-T., Huang, J.-W., Chiang, C.-K., Lawrence, E. C., Levine, K. L., Dabovic, B., Jung, C., Davis, E. C., Madan-Khetarpal, S., Urban, Z. Latent transforming growth factor binding protein 4 regulates transforming growth factor beta receptor stability. Hum. Molec. Genet. 24: 4024-4036, 2015. [PubMed: 25882708] [Full Text: https://doi.org/10.1093/hmg/ddv139]
Urban, Z., Hucthagowder, V., Schurmann, N., Todorovic, V., Zilberberg, L., Choi, J., Sens, C., Brown, C. W., Clark, R. D., Holland, K. E., Marble, M., Sakai, L. Y., Dabovic, B., Rifkin, D. B., Davis, E. C. Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Am. J. Hum. Genet. 85: 593-605, 2009. [PubMed: 19836010] [Full Text: https://doi.org/10.1016/j.ajhg.2009.09.013]