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LTBP4
latent transforming growth factor beta binding protein 4
The LTBP4 gene provides instructions for a protein crucial for maintaining the extracellular matrix and regulating transforming growth factor beta-1 (TGFβ-1) activity. The LTBP4 gene encodes the latent transforming growth factor beta binding protein 4, a key component of the extracellular matrix.
LTBP4 is located on the long (q) arm of chromosome 19, at band 19q13.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The LTBP4 gene, or latent transforming growth factor beta binding protein 4, is vital for the proper structure and function of connective tissues throughout the body. It produces a protein that interacts with the extracellular matrix, a complex network of molecules providing structural support and regulating cell behaviour. Understanding LTBP4's role helps in comprehending conditions affecting connective tissue integrity, such as cutis laxa.
What the gene does
The protein produced from the LTBP4 gene has several critical functions within the extracellular matrix, the complex network surrounding cells. One primary role is to regulate the activity of transforming growth factor beta-1 (TGFβ-1). The LTBP4 protein binds TGFβ-1, storing it in an inactive state within the extracellular matrix until it is needed. Upon release and activation, TGFβ-1 signals cells to direct various processes during growth and development, including the formation of the extracellular matrix itself. Additionally, the LTBP4 protein is indispensable for the correct assembly of elastic fibres. These fibres are crucial protein bundles that lend strength and flexibility to various connective tissues, including those in the skin, lungs, heart, and blood vessels.
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Chromosome location
The LTBP4 gene is situated on chromosome 19, specifically at position 19q13.2. This genomic location indicates its place on the long (q) arm of chromosome 19. The precise arrangement of genetic material at this locus is important for the gene's proper expression and function.
Protein structure
The LTBP4 protein is composed of 1624 amino acids and features a complex arrangement of domains. It includes a Disordered region (amino acids 125-146) followed by an EGF-like 1 domain (amino acids 149-181). Further along, a TB 1 domain (amino acids 287-339) is present, along with an EGF-like 2; calcium-binding domain (amino acids 357-397). Another TB 2 domain (amino acids 407-459) is observed, followed by a second Disordered region (amino acids 474-546). The protein also contains multiple EGF-like domains, many of which are calcium-binding: EGF-like 3 (amino acids 545-586), EGF-like 4; calcium-binding (amino acids 587-628), EGF-like 5; calcium-binding (amino acids 629-670), EGF-like 6; calcium-binding (amino acids 671-708), EGF-like 7; calcium-binding (amino acids 710-751), EGF-like 8; calcium-binding (amino acids 752-793), EGF-like 9; calcium-binding (amino acids 834-877), EGF-like 10; calcium-binding (amino acids 878-919), and EGF-like 11; calcium-binding (amino acids 920-960).
Key variants
Variants within the LTBP4 gene can alter the protein's structure or reduce its functional capacity. These genetic changes can impair the protein's ability to regulate TGFβ-1 or affect the formation of elastic fibres. Pathogenic variants can lead to a range of clinical presentations, particularly those affecting connective tissues.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1307-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies |
c.2029C>T | p.Arg677Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies |
c.2071C>T | p.Arg691Ter | Pathogenic | ★★☆☆ | not provided |
c.4037dup | p.Arg1347fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.254del | p.Leu85fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies |
c.1401G>A | p.Trp467Ter | Pathogenic | ★☆☆☆ | not provided |
c.2440G>T | p.Glu814Ter | Pathogenic | ★☆☆☆ | not provided |
c.457dup | p.Val153fs | Pathogenic | ★☆☆☆ | not provided |
c.109C>T | p.Arg37Ter | Pathogenic | ★☆☆☆ | not provided |
c.338del | p.Pro113fs | Pathogenic | ★☆☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the LTBP4 gene are associated with inherited connective tissue disorders. Specifically, pathogenic variants in LTBP4 cause a form of cutis laxa known as autosomal recessive cutis laxa type 1C (ARCL1C), sometimes referred to as Urban-Rifkin-Davis syndrome. This condition is characterised by loose, sagging skin, lung emphysema, and issues affecting the digestive and urinary systems.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic LTBP4 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The LTBP4 gene is included in several panels within the NHS Genomic Medicine Service (GMS) to aid in diagnosing inherited conditions. It is part of the 'Ehlers Danlos syndrome with a likely monogenic cause' panel (R101) and the 'Foetal anomalies' panel (R21). Its presence on these green-rated panels signifies its established role in these conditions within a clinical diagnostic setting.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the LTBP4 protein?
The LTBP4 protein plays a dual role: it regulates the activity of transforming growth factor beta-1 (TGFβ-1) by storing it in the extracellular matrix, and it is crucial for the formation of elastic fibres that provide strength and flexibility to connective tissues.
Which condition is primarily associated with LTBP4 gene variants?
Variants in the LTBP4 gene are primarily associated with autosomal recessive cutis laxa type 1C (ARCL1C), also known as Urban-Rifkin-Davis syndrome. This condition affects connective tissues, leading to symptoms like loose skin and lung problems.
How is the LTBP4 gene relevant to NHS genomic testing?
The LTBP4 gene is included on NHS Genomic Medicine Service panels, such as those for Ehlers Danlos syndrome with a likely monogenic cause and foetal anomalies. This indicates its clinical significance in diagnosing these conditions within the UK healthcare system.
References
- Noda K, Dabovic B, Takagi K. Latent TGF-β binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5. Proceedings of the National Academy of Sciences of the United States of America. 2013. PMID: 23382201
- Dabovic B, Chen Y, Choi J. Dual functions for LTBP in lung development: LTBP-4 independently modulates elastogenesis and TGF-beta activity. Journal of cellular physiology. 2009. PMID: 19016471
- Urban Z, Hucthagowder V, Schürmann N. Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. American journal of human genetics. 2009. PMID: 19836010
- Adam MP, Bick S, Mirzaa GM. LTBP4-Related Cutis Laxa. 1993. PMID: 26866239