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LTBP4
latent transforming growth factor beta binding protein 4
The LTBP4 gene provides instructions for a protein that plays a vital role in forming elastic fibres and regulating the activity of transforming growth factor beta-1 (TGFβ-1) in the extracellular matrix. LTBP4 is essential for maintaining the structure and flexibility of connective tissues throughout the body.
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 encodes the latent transforming growth factor beta binding protein 4. This protein is a key component of the extracellular matrix, the complex network surrounding cells that provides structural support and biochemical cues.
Its primary roles involve regulating signalling pathways and contributing to the formation of elastic fibres, which are crucial for the strength and flexibility of various connective tissues, including those in the skin, lungs, and blood vessels.
What the gene does
The LTBP4 protein performs several critical functions within the extracellular matrix. One significant role is controlling the activity of transforming growth factor beta-1 (TGFβ-1). LTBP4 binds TGFβ-1, anchoring it within the extracellular matrix, which keeps the growth factor in an inactive state. When TGFβ-1 is released from LTBP4, it becomes active and initiates cellular signals that influence cell growth, development, and the organisation of the extracellular matrix itself.
Beyond TGFβ-1 regulation, the LTBP4 protein is also fundamental for the proper assembly of elastic fibres. These fibres are vital for providing resilience and recoil to tissues like skin, lungs, the heart, and blood vessels. Impaired LTBP4 function can therefore affect the structural integrity and flexibility of these crucial connective tissues.
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Chromosome location
The LTBP4 gene is located on chromosome 19, specifically at position 19q13.2. This indicates its position on the long (q) arm of chromosome 19, within band 13.2.
Protein structure
The LTBP4 protein is composed of 1624 amino acids. It features several distinct domains and regions that contribute to its function. These include a Disordered region (amino acids 125-146), followed by an EGF-like 1 domain (amino acids 149-181) and a TB 1 domain (amino acids 287-339). Further along the protein are an EGF-like 2; calcium-binding domain (amino acids 357-397) and a TB 2 domain (amino acids 407-459). Another Disordered region is present (amino acids 474-546), preceding a series of EGF-like domains: 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 in the LTBP4 gene can alter the function of the LTBP4 protein, leading to a range of effects on connective tissue integrity and TGFβ-1 signalling. These genetic changes can result in conditions inherited in an autosomal recessive pattern, meaning an individual must inherit two affected copies of the gene to develop the condition.
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.1630del | p.Arg544fs | Pathogenic | ★☆☆☆ | Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies |
c.2440G>T | p.Glu814Ter | Pathogenic | ★☆☆☆ | not provided |
c.457dup | p.Val153fs | Pathogenic | ★☆☆☆ | not provided |
c.109C>T | p.Arg37Ter | 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
Pathogenic variants in the LTBP4 gene are associated with autosomal recessive cutis laxa type 1C (ARCL1C), also known as Urban-Rifkin-Davis syndrome. This condition is characterised by features such as loose and sagging skin, lung disease (emphysema), and abnormalities affecting the digestive and urinary systems. At least 20 different variants in the LTBP4 gene have been identified in individuals with cutis laxa.
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 part of national genomic testing strategies in the UK. It is currently included on the NHS Genomic Medicine Service's PanelApp for 'Ehlers Danlos syndrome with a likely monogenic cause' (R101) and 'Foetal anomalies' (R21), both of which are rated as green, indicating strong evidence for gene-disease association.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the LTBP4 gene?
The LTBP4 gene produces a protein crucial for the extracellular matrix, where it helps regulate the growth factor TGFβ-1 and is essential for forming elastic fibres that provide strength and flexibility to connective tissues.
What condition is associated with LTBP4 gene variants?
Variants in the LTBP4 gene are associated with autosomal recessive cutis laxa type 1C (ARCL1C), also known as Urban-Rifkin-Davis syndrome. This condition involves loose skin, lung issues, and digestive/urinary abnormalities.
How is cutis laxa type 1C inherited?
Cutis laxa type 1C, caused by LTBP4 variants, is inherited in an autosomal recessive manner. This means an individual must inherit two copies of the altered gene, one from each parent, to develop the condition.
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