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CRLF1 gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

CRLF1 gene

The CRLF1 gene is responsible for producing a protein complex that regulates the development and maintenance of the nervous system.

Normal Function

The CRLF1 gene provides instructions for making a protein called cytokine receptor-like factor 1 (CRLF1). This protein partners with a similar protein called cardiotrophin-like cytokine factor 1 (CLCF1) to form the CRLF1/CLCF1 protein complex. This complex binds to a receptor protein known as the ciliary neurotrophic factor receptor (CNTFR) on the surface of many cell types, triggering signaling that affects cell development and function.

The CNTFR signaling pathway is primarily involved in the development and maintenance of the nervous system, including:

  • Promoting the survival of nerve cells (neurons), particularly motor neurons.
  • Regulating the sympathetic nervous system, specifically the control of sweating in response to temperature changes.
  • Supporting the development and maturation of nerve cells that control sweat glands.

Studies suggest this pathway may also be involved in the body's inflammatory response and the development and maintenance of bone tissue.

Health Conditions Related to Genetic Changes

Cold-induced sweating syndrome

At least 10 mutations in the CRLF1 gene have been reported to cause cold-induced sweating syndrome, a rare condition characterized by problems with regulating body temperature and other abnormalities. When caused by CRLF1 mutations, it is known as CISS1.

Mutations in the CRLF1 gene lead to the production of a nonfunctional version of the CRLF1 protein or significantly reduce its production. This prevents the protein from interacting with CLCF1 and binding to CNTFR, effectively disabling the CNTFR signaling pathway. Researchers believe this failure of signaling underlies the major features of the syndrome, including:

  • Abnormal sweating patterns.
  • Problems with body temperature regulation.
  • Distinctive facial features and facial muscle weakness.
  • Skeletal abnormalities.

Other Names for This Gene

  • CISS
  • CISS1
  • Class I cytokine receptor
  • CLF
  • CLF-1
  • Cytokine receptor-like factor 1
  • Cytokine type 1 receptor CRLP-1
  • Cytokine-like factor 1
  • zcytor5

Frequently Asked Questions

CISS1 caused by CRLF1 follows an autosomal recessive pattern. Both parents are typically carriers, each possessing one mutated copy. For each future pregnancy, there is a 25 % chance the child will be affected, a 50 % chance of being an asymptomatic carrier, and a 25 % chance of inheriting two normal copies. Carrier testing for siblings and options such as prenatal diagnosis or pre‑implantation genetic testing are available for family planning.
Key clues include excessive sweating triggered by mild cold exposure, difficulty maintaining body temperature (feeling unusually cold or hot), distinctive facial features such as a broad forehead, deep-set eyes, and a small chin, as well as joint contractures or skeletal abnormalities. When these signs appear together, especially in a child, CRLF1 testing should be considered.
clinician can order a single‑gene test for CRLF1 or include it in a broader neurodevelopmental panel. No special preparation (fasting, medication changes) is required; a blood sample is typically drawn. A genetics professional will review the results, which may be pathogenic, likely pathogenic, or a variant of uncertain significance, and discuss implications for the patient and family.
Management is symptomatic. Strategies include wearing layered, breathable clothing, using portable cooling devices in warm environments, and avoiding sudden temperature changes. Physical therapy can help with joint stiffness. In some cases, medications that modulate autonomic function (e.g., anticholinergics) are tried, but benefits vary and side effects must be monitored.
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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