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IFT140
intraflagellar transport 140
The IFT140 gene provides instructions for a protein critical to the formation and maintenance of cilia, microscopic structures vital for cell signalling and various bodily functions. IFT140 encodes a protein essential for intraflagellar transport (IFT), a process that builds and maintains cilia.
IFT140 is located on the short (p) arm of chromosome 16, at band 16p13.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The IFT140 gene, or intraflagellar transport 140, is instrumental in producing a protein that forms part of the intraflagellar transport (IFT) system. This system is responsible for constructing and maintaining cilia, which are small, finger-like projections found on the surface of many cell types.
Cilia play a fundamental role in cell-to-cell communication and are vital for the normal development and function of numerous tissues, including the kidneys, retina, and bones. Pathogenic variants within the IFT140 gene can disrupt these critical processes, leading to a range of genetic conditions, often characterised by their impact on ciliary function.
What the gene does
The protein encoded by the IFT140 gene is a component of the IFT-A complex, which is one of two main protein complexes that make up IFT particles. These particles facilitate the movement of materials along cilia, a process known as intraflagellar transport.
Intraflagellar transport is essential for the assembly and ongoing maintenance of cilia. Cilia themselves are involved in various cellular signalling pathways, relaying information within and between cells. This includes their role in photoreceptors of the retina for normal vision, and their influence on bone development. Disturbances in IFT140 function, often due to genetic changes, can impair the proper assembly of the IFT-A complex, thereby affecting ciliary structure and overall cellular function.
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Chromosome location
The IFT140 gene is located on chromosome 16 at position 16p13.3. This specific genomic address indicates its precise position on the short arm of chromosome 16. The gene's location is consistent across the human population.
Protein structure
The IFT140 protein is composed of 1462 amino acids and features a distinctive domain architecture. It includes several WD repeats, specifically WD 1 (amino acids 4-48), WD 2 (amino acids 51-90), WD 3 (amino acids 93-132), WD 4 (amino acids 139-188), WD 5 (amino acids 221-259), WD 6 (amino acids 266-305), and WD 7 (amino acids 322-361). Additionally, the protein contains multiple Tetratricopeptide Repeat (TPR) domains: TPR 1 (amino acids 772-807), TPR 2 (amino acids 869-904), TPR 3 (amino acids 906-934), TPR 4 (amino acids 955-988), TPR 5 (amino acids 1010-1043), TPR 6 (amino acids 1078-1111), TPR 7 (amino acids 1123-1156), and TPR 8 (amino acids 1189-1222). These domains are crucial for its interactions with other proteins within the IFT complex.
Key variants
Variants within the IFT140 gene can impact the structure and function of the IFT140 protein, potentially disrupting its role in cilia formation and maintenance. These genetic changes can alter protein shape or interfere with its interactions with other IFT proteins, leading to impaired ciliary function. As IFT140-related conditions are inherited in an autosomal recessive manner, an individual typically needs to inherit two pathogenic variants, one from each parent, to develop a 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.1010-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1039C>T | p.Arg347Ter | Pathogenic | ★★☆☆ | Saldino-Mainzer syndrome |
c.1147C>T | p.Gln383Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Saldino-Mainzer syndrome |
c.1246C>T | p.Gln416Ter | Pathogenic | ★★☆☆ | Retinitis pigmentosa 80 |
c.1250_1271dup | p.Ser425fs | Pathogenic/Likely pathogenic | ★★☆☆ | Retinal dystrophy |
c.1359_1359+3delinsAC | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1377G>A | p.Trp459Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Saldino-Mainzer syndrome |
c.1380del | p.Asn460fs | Pathogenic | ★★☆☆ | Saldino-Mainzer syndrome |
c.1422_1423insAA | p.Arg475fs | Pathogenic | ★★☆☆ | Retinitis pigmentosa 80 |
c.1451C>T | p.Thr484Met | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 80 |
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 IFT140 gene are associated with a spectrum of inherited conditions, predominantly affecting ciliary function. One notable condition is Mainzer-Saldino syndrome, an autosomal recessive disorder characterised by kidney disease, eye problems, and skeletal abnormalities. Other related conditions can include asphyxiating thoracic dystrophy and retinitis pigmentosa, all stemming from disruptions in the vital role of IFT140 in cilia.
Inheritance pattern
Conditions caused by pathogenic IFT140 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 IFT140 gene is recognised within the NHS Genomic Medicine Service due to its association with several conditions. It is listed on multiple NHS England National Genomic Test Directory panels, including those for Clefting, Cystic kidney disease, DDG2P, Foetal anomalies (R21), Rare multisystem ciliopathy disorders, Rare syndromic craniosynostosis or isolated multisuture synostosis (R100), Renal ciliopathies, Retinal disorders (R32), Skeletal ciliopathies, Skeletal dysplasia (R104), and Thoracic dystrophies.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the IFT140 gene?
The IFT140 gene provides instructions for a protein that is a crucial component of the intraflagellar transport (IFT) system. This system is responsible for the assembly and maintenance of cilia, which are microscopic, finger-like projections on cell surfaces vital for cell signalling.
How is Mainzer-Saldino syndrome connected to the IFT140 gene?
Mainzer-Saldino syndrome is an autosomal recessive condition linked to pathogenic variants in the IFT140 gene. These variants can impair the function of the IFT140 protein, leading to kidney disease, eye problems, and skeletal abnormalities characteristic of the syndrome.
What does autosomal recessive inheritance mean for IFT140-related conditions?
Autosomal recessive inheritance means that an individual must inherit two copies of a pathogenic IFT140 variant, one from each parent, to develop a condition. Individuals with only one pathogenic variant are typically carriers and do not show symptoms.
References
- Schmidts M, Frank V, Eisenberger T. Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease. Human mutation. 2013. PMID: 23418020
- Behal RH, Miller MS, Qin H. Subunit interactions and organization of the Chlamydomonas reinhardtii intraflagellar transport complex A proteins. The Journal of biological chemistry. 2012. PMID: 22170070
- Jonassen JA, SanAgustin J, Baker SP. Disruption of IFT complex A causes cystic kidneys without mitotic spindle misorientation. Journal of the American Society of Nephrology : JASN. 2012. PMID: 22282595
- Perrault I, Saunier S, Hanein S. Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations. American journal of human genetics. 2012. PMID: 22503633