LTBP4
protein-codinglatent transforming growth factor beta binding protein 4, the group of Latent transforming growth factor beta binding proteins
Gene summary
The protein encoded by this gene binds transforming growth factor beta (TGFB) as it is secreted and targeted to the extracellular matrix. TGFB is biologically latent after secretion and insertion into the extracellular matrix, and sheds TGFB and other proteins upon activation. Defects in this gene may be a cause of cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~36.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013170
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013170
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013170
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013170
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0013170
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Dermatologic; Gastrointestinal; Genitourinary; Musculoskeletal; Pulmonary
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LTBP4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001042545.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 17 | 290 | 7 | 314 | ||
| missense | 1 | 1 | 486 | 34 | 6 | 528 |
| nonsense | 19 | 5 | 1 | 25 | ||
| start loss | 1 | 1 | ||||
| frameshift | 22 | 6 | 2 | 1 | 31 | |
| splice donor/acceptor (+/-2bp) | 10 | 10 | 20 | |||
| Total | 42 | 23 | 515 | 326 | 13 | 919 |
Highest pathogenic variant AF is 0.000037189297
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001036010.1 | 30 | MANE Select | |
| Ensembl | ENSP00000380031.5 | 30 | MANE Select | |
| RefSeq | NP_001036009.1 | 33 | Standard | |
| RefSeq | NP_003564.2 | 33 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Extracellular matrix organization
- Molecules associated with elastic fibres
- Elastic fibre formation
Biological Process
- regulation of cell growth
- protein folding
- transforming growth factor beta receptor signaling pathway
- multicellular organism development
- regulation of transforming growth factor beta receptor signaling pathway
Molecular Function
- transforming growth factor beta-activated receptor activity
- integrin binding
- extracellular matrix structural constituent
- calcium ion binding
- protein binding
Cellular Component
- extracellular region
- extracellular space
- extracellular matrix
- collagen-containing extracellular matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000308370
- Coding exons
- 34
- Length
- 36937
- Individuals with no LoFs
- 514
- Homozygous LoFs
- 124210
- Heterozygous LoFs
- 6
- Defined
- 124730
- p
- 0.936
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.35 | 837 | 1.05e+3 | 0.796 | 0.0000665 | 10249 |
| Missense (PolyPhen) | 321 | 444.92 | 0.72148 | 4442 | ||
| Synonymous | 1.21 | 407 | 439 | 0.927 | 0.0000289 | 3365 |
| Loss of Function | 6.65 | 19 | 85.3 | 0.223 | 0.00000447 | 897 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 1.0 | 0.90 | notable |
| Latino/Admixed American | 1.0 | 0.96 | notable |
| Ashkenazi Jewish | 1.0 | 0.95 | notable |
| East Asian | 1.0 | 0.98 | notable |
| Finnish | 1.0 | 0.95 | notable |
| European (Non-Finnish) | 1.0 | 0.92 | notable |
| South Asian | 1.0 | 0.96 | notable |
| Other | 1.0 | 0.94 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space. Associates specifically via disulfide bonds with the Latency- associated peptide (LAP), which is the regulatory chain of TGF- beta, and regulates integrin-dependent activation of TGF-beta. {ECO:0000250|UniProtKB:Q14766}.;
- Disease
- DISEASE: Urban-Rifkin-Davis syndrome (URDS) [MIM:613177]: A syndrome characterized by disrupted pulmonary, gastrointestinal, urinary, musculoskeletal, craniofacial and dermal development. Clinical features include cutis laxa, mild cardiovascular lesions, respiratory distress with cystic and atelectatic changes in the lungs, and diverticulosis, tortuosity and stenosis at various levels of the intestinal tract. Craniofacial features include microretrognathia, flat midface, receding forehead and wide fontanelles. {ECO:0000269|PubMed:19836010}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Duchenne muscular dystrophy (DMD) [MIM:310200]: Most common form of muscular dystrophy; a sex-linked recessive disorder. It typically presents in boys aged 3 to 7 year as proximal muscle weakness causing waddling gait, toe-walking, lordosis, frequent falls, and difficulty in standing up and climbing up stairs. The pelvic girdle is affected first, then the shoulder girdle. Progression is steady and most patients are confined to a wheelchair by age of 10 or 12. Flexion contractures and scoliosis ultimately occur. About 50% of patients have a lower IQ than their genetic expectations would suggest. There is no treatment. {ECO:0000269|PubMed:23440719, ECO:0000269|PubMed:25641372}. Note=The gene represented in this entry may act as a disease modifier. DMD patients homozygous for the IAAM haplotype consisting of Ile-194, Ala-787, Ala-820 and Met-1141 remain ambulatory significantly longer than those heterozygous or homozygous for the VTTT haplotype consisting of Val-194, Thr-787, Thr-820 and Thr-1141. This may be due to increased binding to TGFB1, resulting in TGFB1 sequestration in the extracellular matrix and reduced TGFB1 signaling which has been linked to improved muscle function and regeneration. {ECO:0000269|PubMed:23440719}.;
Recessive Scores
- pRec
- 0.123
Essentials
- Essential (CRISPR2)
- S
- Indispensability pred.
- E
- Indispensability score
- 0.880
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |