HGNC Approved Gene Symbol: LTBP1
Cytogenetic location: 2p22.3 Genomic coordinates (GRCh38): 2:32,946,953-33,399,509 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p22.3 | Cutis laxa, autosomal recessive, type IIE | 619451 | Autosomal recessive | 3 |
All 3 transforming growth factor beta isoforms (e.g., TGFB1; 190180) are secreted as large latent complexes that have no biologic activity. The large latent complex has 3 components: a disulfide-bonded homodimer of mature TGFB associated noncovalently with latency-associated proteins (LAPs), which are homodimers of the N-terminal fragment of precursor TGFB, and a covalently attached latent TGFB-binding protein (LTBP), such as LTBP1. LAPs are sufficient to render the mature TGFB homodimer inactive, and removal of both the LAPs and LTBP, or modulation of their interaction, is essential for TGFB function (review by Oklu and Hesketh, 2000).
Kanzaki et al. (1990) cloned a cDNA encoding human LTBP1. The structure of human LTBP1 resembles fibrillin in that it includes 16 epidermal growth factor-like repeats and 3 copies of a novel 8-cysteine motif.
Using PCR, Koski et al. (1999) detected variable expression of 2 major splice variants of LTBP1 in human cell lines. The variants, LTBP1L and LTBP1S, differed in 5-prime splicing and encode proteins with long and short N-terminal ends, respectively.
In their review, Oklu and Hesketh (2000) described LTBP1 splice variants common to both LTBP1L and LTBP1S: LTBP1-delta-42, which encodes an isoform lacking EGF-like domain-12, and LTBP1-delta-53, which encodes a protein that lacks the eighth cysteine of the first 8-cysteine domain. LTBP1L has an additional splice variant, LTBP1-delta-55, which encodes a protein lacking 2 putative N-glycosylation sites.
Using quantitative RT-PCR, Oklu et al. (2011) examined the expression of 3 alternatively spliced isoforms of LTBP1 as well as the expression of LTBP1L and LTBP1S isoforms and total LTBP1. They found that total LTBP1 mRNA in advanced atherosclerotic lesions was approximately 2.4-fold the amount present in early lesions. In most tissues, LTBP1-delta-55 and LTBP1L were minor components of LTBP1.
By sequencing the 5-prime flanking regions of LTBP1L and LTBP1S, Koski et al. (1999) determined that LTBP1L is transcribed independently from a promoter upstream of the LTBP1S promoter. Both promoters lack TATA or CAAT boxes, but they both have binding sites for AP1 (see 165160), GATA1 (305371), and OCT1 (POU2F1; 164175). Both promoters also have unique regulatory elements, including SP1 (189906)-binding sites in the LTBP1L promoter and an NF-kappa-B (see 164011)-binding site and a TGFB inhibitory element (TIE) in the LTBP1S promoter.
Using a cDNA clone for LTBP1, Stenman et al. (1994) assigned the gene to chromosome 2 by study of a panel of well-defined human/rodent somatic cell hybrid lines and further localized the gene to 2p12-q22 by study of 3 hybrid lines containing partially overlapping fragments of chromosome 2.
Stumpf (2021) mapped the LTBP1 gene to chromosome 2p22.3 based on an alignment of the LTBP1 sequence (GenBank BC130289) with the genomic sequence (GRCh38).
By exome sequencing in 4 unrelated consanguineous families segregating autosomal recessive cutis laxa (ARCL2E; 619451), Pottie et al. (2021) identified homozygosity for truncating variants in the LTBP1 gene (150390.0001-150390.0004) in the 8 affected children. Segregation in all families was confirmed by Sanger sequencing, and none of the variants were present in public variant databases. Functional analysis demonstrated that different variants produce distinct molecular signatures in the development of the extracellular matrix and TGFB (190180) signaling.
Pottie et al. (2021) generated 2 Ltbp1-deficient zebrafish models: delta-29 mutants with a 1-bp deletion in exon 29, which lack 2 TGF-binding domains, 3 calcium-binding EGF-like domains, and 1 EGF-like domain at the C terminus; and delta-35 mutants with a 10-bp deletion in exon 35, which lack the last calcium-binding EGF-like domain and the last EGF-like domain. both homozygous mutant zebrafish models had abnormal dermal collagen architecture showing a folded plywood-like organization, indicating skin redundancy, the hallmark phenotype of cutis laxa syndrome (see MOLECULAR GENETICS), as well as abnormal fibrillogenesis in the intervertebral ligament. Ltbp1 delta-29 zebrafish also had vertebral hypomineralization, voluminous vertebrae, and ectopic bone formation, whereas Ltbp1 delta-35 zebrafish showed normal mineralization but still displayed ectopic bone formed by intramembranous ossification. However, neither zebrafish model exhibited craniofacial abnormalities or craniosynostosis.
In a 3-year-old Turkish girl (family 1) with cutis laxa (ARCL2E; 619451), Pottie et al. (2021) identified homozygosity for a 1-bp deletion (c.4844del, NM_206943.4) in the LTBP1 gene, causing a frameshift predicted to result in a premature termination codon (Asn1615IlefsTer23) within the C-terminal third EGF-like domain. The deletion was detected by whole-exome sequencing, and Sanger sequencing confirmed heterozygosity for the deletion in her unaffected first-cousin parents. The deletion was not found in public variant databases. LTBP1 mRNA expression in patient dermal fibroblasts was equal to that in control fibroblasts, and rudimentary LTBP1 fibers were present at 9 days postconfluency. Functional analysis showed that the variant results in an altered LTBP1 protein that is only loosely anchored in the microfibrillar network, and causes increased extracellular-matrix deposition associated with excessive TGFB (190180) growth factor activation and signaling.
In 4 children with cutis laxa (ARCL2E; 619451) from 2 sibships of a multiply consanguineous Pakistani pedigree (family 2), Pottie et al. (2021) identified homozygosity for a c.4431T-A transversion (c.4431T-A, NM_206943.4) in the LTBP1 gene, resulting in a cys1477-to-ter (C1477X) substitution at a highly conserved residue within the thirteenth calcium-binding EGF-like domain. The mutation was detected by whole-exome sequencing, and Sanger sequencing confirmed heterozygosity for the mutation in the unaffected parents. The mutation was not found in public variant databases.
In a Pakistani sister and brother (family 3) with cutis laxa (ARCL2E; 619451), Pottie et al. (2021) identified homozygosity for a 1-bp duplication (c.3991dup, NM_206943.4) in the LTBP1 gene, causing a frameshift predicted to result in a premature termination codon (Thr1331AsnfsTer22) within the twelfth calcium-binding EGF-like domain. The mutation was detected by whole-exome sequencing, and Sanger sequencing confirmed heterozygosity for the mutation in the unaffected consanguineous parents. The variant was not found in public variant databases.
In a 1.75-year-old Saudi Arabian girl (family 4) with cutis laxa (ARCL2E; 619451), Pottie et al. (2021) identified homozygosity for a c.1342C-T transition (c.1342C-T, NM_206943.4) in the LTBP1 gene, resulting in a gln448-to-ter (Q448X) substitution at a highly conserved residue within the second EGF-like domain. The mutation was detected by whole-exome sequencing, and Sanger sequencing confirmed heterozygosity for the deletion in the unaffected consanguineous parents. The mutation was not found in public variant databases. RT-qPCR in cultured dermal fibroblasts from the patient revealed that LTBP1 expression was completely abolished but could be partially rescued by cyclohexamide treatment, indicative of nonsense-mediated decay.
Kanzaki, T., Olofsson, A., Moren, A., Wernstedt, C., Hellman, U., Miyazono, K., Claesson-Welsh, L., Heldin, C. H. TGF-beta 1 binding protein: a component of the large latent complex of TGF-beta 1 with multiple repeat sequences. Cell 61: 1051-1061, 1990. [PubMed: 2350783] [Full Text: https://doi.org/10.1016/0092-8674(90)90069-q]
Koski, C., Saharinen, J., Keski-Oja, J. Independent promoters regulate the expression of two amino terminally distinct forms of latent transforming growth factor-beta binding protein-1 (LTBP-1) in a cell type-specific manner. J. Biol. Chem. 274: 32619-32630, 1999. [PubMed: 10551816] [Full Text: https://doi.org/10.1074/jbc.274.46.32619]
Oklu, R., Hesketh, R., Wicky, S., Metcalfe, J. C. Expression of mRNA isoforms of latent transforming growth factor-beta binding protein-1 in coronary atherosclerosis and human tissues. Biochem. Genet. 49: 213-225, 2011. [PubMed: 21161366] [Full Text: https://doi.org/10.1007/s10528-010-9400-x]
Oklu, R., Hesketh, R. The latent transforming growth factor beta binding protein (LTBP) family. Biochem. J. 352: 601-610, 2000. [PubMed: 11104663]
Pottie, L., Adamo, C. S., Beyens, A., Lutke, S., Tapaneeyaphan, P., De Clercq, A., Salmon, P. L., De Rycke, R., Gezdirici, A., Gulec, E. Y., Khan, N., Urquhart, J. E., and 17 others. Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome. Am. J. Hum. Genet. 108: 1095-1114, 2021. Note: Erratum: Am. J. Hum. Genet. 108: 2386-2388, 2021. [PubMed: 33991472] [Full Text: https://doi.org/10.1016/j.ajhg.2021.04.016]
Stenman, G., Sahlin, P., Olofsson, A., Geurts van Kessel, A., Miyazono, K. Assignment of the gene encoding the latent TGF-beta-1-binding protein (LTBP1) to human chromosome 2, region p12-q22. Cytogenet. Cell Genet. 66: 117-119, 1994. [PubMed: 8287682] [Full Text: https://doi.org/10.1159/000133680]
Stumpf, A. M. Personal Communication. Baltimore, Md. 07/21/2021.