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CLCF1 gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

CLCF1 gene

The CLCF1 gene produces a protein critical for nervous system development and maintenance, with mutations linked to cold-induced sweating syndrome.

Normal Function

The CLCF1 gene provides instructions for making a protein called cardiotrophin-like cytokine factor 1 (CLCF1). This protein partners with a similar protein called cytokine receptor-like factor 1 (CRLF1), which is produced from the CRLF1 gene. Together, these two proteins form a unit known as the CRLF1/CLCF1 protein complex. This complex attaches (binds) to a receptor protein known as the ciliary neurotrophic factor receptor (CNTFR) on the surface of many types of cells. When the CRLF1/CLCF1 protein complex is bound to CNTFR, it triggers signaling inside the cell that affects cell development and function.

The CNTFR signaling pathway is primarily involved in the development and maintenance of the nervous system. It promotes the survival of nerve cells (neurons), particularly nerve cells that control muscle movement (motor neurons). The CNTFR pathway also plays a role in a part of the nervous system called the sympathetic nervous system, specifically in the regulation of sweating in response to temperature changes and other factors. This signaling pathway appears to be critical for the normal development and maturation of nerve cells that control the activity of sweat glands.

Studies suggest that the CNTFR signaling pathway also has functions outside the nervous system. It may be involved in the body's inflammatory response, which helps fight infection and facilitate tissue repair following an injury. This pathway may also be important for the development and maintenance of bone tissue.

Health Conditions Related to Genetic Changes

Cold-induced sweating syndrome

At least four mutations in the CLCF1 gene have been reported to cause cold-induced sweating syndrome, a rare condition characterized by problems with regulating body temperature and other abnormalities affecting many parts of the body. When this condition is caused by CLCF1 gene mutations, it is known as CISS2.

Mutations in the CLCF1 gene lead to the production of a nonfunctional version of the CLCF1 protein. The defective protein is unable to interact with the CLRF1 protein and bind to CNTFR, which disables the CNTFR signaling pathway. Researchers believe that a failure of CNTFR signaling underlies the major features of cold-induced sweating syndrome, including abnormal sweating patterns, distinctive facial features, facial muscle weakness, and skeletal abnormalities.

Other Names for This Gene

  • B-cell stimulating factor 3
  • B-cell stimulatory factor 3
  • BSF-3
  • BSF3
  • cardiotrophin-like cytokine
  • cardiotrophin-like cytokine factor 1
  • CISS2
  • CLC
  • CLCF1_HUMAN
  • CRLF1 associated cytokine-like factor 1
  • neurotrophin-1/B-cell stimulating factor-3
  • NNT-1
  • NNT-1/BSF-3
  • NNT1
  • novel neurotrophin-1
  • NR6

Frequently Asked Questions

Testing is recommended for individuals with the characteristic cold‑sweat phenotype, especially if there is a family history of similar symptoms. A peripheral blood draw (or saliva sample) provides DNA for either targeted CLCF1 sequencing or a multigene panel for neuro‑developmental disorders.
Management is largely symptomatic: wearing breathable clothing, using antiperspirants, and in severe cases, botulinum toxin injections to affected areas. No approved drugs directly modulate the CNTFR pathway, but research into CNTF analogs is ongoing; participation in clinical trials should be discussed with a neurologist.
Yes, some patients develop mild skeletal abnormalities (e.g., scoliosis or short stature) and occasional neuro‑psychiatric issues such as anxiety or learning difficulties. Regular orthopedic evaluations and developmental screening are advised to catch these associated problems early.
The classic presentation includes profuse sweating triggered by cold exposure, often beginning in childhood, together with mild facial dysmorphism, joint laxity, and sometimes delayed motor milestones. If excessive sweating is disproportionate to temperature changes or is accompanied by unexplained growth or bone abnormalities, clinicians should consider CLCF1 testing.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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