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CRLF1
cytokine receptor like factor 1
The CRLF1 gene encodes a protein crucial for nervous system development and function, particularly in regulating sweating and motor neuron survival. The CRLF1 gene provides instructions for the cytokine receptor-like factor 1 protein.
CRLF1 is located on the short (p) arm of chromosome 19, at band 19p12. Arm ratio per GRCh38 - banding schematic.
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Overview
The CRLF1 gene provides the blueprint for the cytokine receptor-like factor 1 protein. This protein plays an important role in cellular communication by forming a complex with another protein, CLCF1. This complex then interacts with the ciliary neurotrophic factor receptor (CNTFR) on cell surfaces, triggering internal signalling cascades.
These signalling pathways are primarily involved in the healthy development and ongoing function of the nervous system. Research also suggests potential roles for CRLF1 in inflammatory responses and bone tissue maintenance, although these areas require further investigation.
What the gene does
The CRLF1 protein partners with the cardiotrophin-like cytokine factor 1 (CLCF1) protein. Together, they form a complex known as CRLF1/CLCF1. This complex's primary function is to bind to the ciliary neurotrophic factor receptor (CNTFR) located on the surface of various cell types.
Upon binding, the CRLF1/CLCF1 complex activates internal cellular signalling pathways. These pathways are crucial for the development and survival of nerve cells, especially motor neurons which control muscle movement. They also contribute to the sympathetic nervous system, influencing the regulation of sweating in response to environmental changes. Proper functioning of this signalling pathway appears essential for the normal maturation of nerve cells that govern sweat gland activity. Additionally, the CNTFR signalling pathway may contribute to the body's inflammatory response and bone development, though these roles are less understood.
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Chromosome location
The CRLF1 gene is situated on chromosome 19, specifically at position 19p12. This chromosomal location indicates where the gene can be found within the human genome.
Protein structure
The CRLF1 protein consists of 422 amino acids and contains several key structural features. It includes an Ig-like C2-type domain spanning amino acids 38-131, followed by two Fibronectin type-III domains: Fibronectin type-III 1 from amino acids 137-232, and Fibronectin type-III 2 from amino acids 237-341. A WSXWS motif is located between amino acids 327-331. The protein also contains two disordered regions: one from amino acids 332-363 and another at the C-terminus from amino acids 399-422.
Key variants
Variants within the CRLF1 gene can alter the production or function of the cytokine receptor-like factor 1 protein. These genetic changes may disrupt the protein's ability to partner with CLCF1 or to effectively bind to the CNTFR, thereby impacting downstream signalling pathways. Such disruptions can have consequences for nervous system development and function.
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.31_53del | p.Gln11fs | Pathogenic | ★★☆☆ | Cold-induced sweating syndrome |
c.397+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Cone-rod dystrophy 12 |
c.531G>A | p.Trp177Ter | Pathogenic | ★★☆☆ | Cold-induced sweating syndrome 1 |
c.713del | p.Pro238fs | Pathogenic | ★★☆☆ | Cold-induced sweating syndrome 1 |
c.713dup | p.Pro239fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.983dup | p.Ser328fs | Pathogenic | ★★☆☆ | Cold-induced sweating syndrome 1 |
g.(?_18709222)_(18710676_?)del | - | Pathogenic | ★☆☆☆ | not provided |
c.322C>T | p.Gln108Ter | Pathogenic | ★☆☆☆ | not provided |
c.676dup | p.Thr226fs | Pathogenic | ★☆☆☆ | Cold-induced sweating syndrome 1 |
c.985dup | p.Glu329fs | Pathogenic | - | Cold-induced sweating syndrome 1 |
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 CRLF1 gene are associated with inherited conditions that primarily affect the nervous system. One such condition linked to CRLF1 variants is cold-induced sweating syndrome. This syndrome is characterised by difficulties in regulating body temperature and other systemic abnormalities.
No disease links recorded for this gene in our reference set.
UK clinical status
The CRLF1 gene is included on several NHS Genomic Medicine Service national test directories. It is listed with a 'green' RAG (Red Amber Green) rating for the Arthrogryposis (R83) and Foetal anomalies (R21) panels, indicating that it is routinely considered for sequencing in the context of these conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the CRLF1 gene?
The CRLF1 gene provides instructions for a protein that forms a complex with CLCF1. This complex binds to the CNTFR receptor, initiating signalling pathways crucial for nervous system development, particularly motor neuron survival and sweat regulation.
Which conditions are associated with CRLF1 gene variants?
Variants in the CRLF1 gene are associated with cold-induced sweating syndrome, a condition affecting temperature regulation and other bodily functions.
Is CRLF1 considered on NHS genetic testing panels?
Yes, CRLF1 is a 'green' gene on NHS Genomic Medicine Service national test directories for Arthrogryposis (R83) and Foetal anomalies (R21), meaning it's routinely assessed for these conditions.
References
- Herholz J, Meloni A, Marongiu M. Differential secretion of the mutated protein is a major component affecting phenotypic severity in CRLF1-associated disorders. European journal of human genetics : EJHG. 2011. PMID: 21326283
- Kass DJ. Cytokine-like factor 1 (CLF1): life after development? Cytokine. 2011. PMID: 21715184
- Hahn AF, Waaler PE, Kvistad PH. Cold-induced sweating syndrome: CISS1 and CISS2: manifestations from infancy to adulthood. Four new cases. Journal of the neurological sciences. 2010. PMID: 20400119
- Dagoneau N, Bellais S, Blanchet P. Mutations in cytokine receptor-like factor 1 (CRLF1) account for both Crisponi and cold-induced sweating syndromes. American journal of human genetics. 2007. PMID: 17436251
- Crisponi L, Crisponi G, Meloni A. Crisponi syndrome is caused by mutations in the CRLF1 gene and is allelic to cold-induced sweating syndrome type 1. American journal of human genetics. 2007. PMID: 17436252
- Hahn AF, Jones DL, Knappskog PM. Cold-induced sweating syndrome: a report of two cases and demonstration of genetic heterogeneity. Journal of the neurological sciences. 2006. PMID: 16952376
- Knappskog PM, Majewski J, Livneh A. Cold-induced sweating syndrome is caused by mutations in the CRLF1 gene. American journal of human genetics. 2003. PMID: 12509788
- Elson GC, Graber P, Losberger C. Cytokine-like factor-1, a novel soluble protein, shares homology with members of the cytokine type I receptor family. Journal of immunology (Baltimore, Md. : 1950). 1998. PMID: 9686600