RETmutant

RETmutant refers to an allele of the RET gene that carries mutations altering the function of the RET receptor tyrosine kinase. The RET gene encodes a transmembrane receptor involved in development of the enteric nervous system, kidneys, and neural crest derivatives. Signaling is mediated by ligands of the GDNF family in conjunction with GFRalpha co-receptors, leading to RET activation and downstream pathways that regulate cell growth and differentiation.

Pathogenic RET mutations can be gain-of-function or loss-of-function. Gain-of-function mutations cause constitutive RET signaling and are strongly associated with hereditary cancer syndromes, most notably multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma. The best-known substitutions include C634R (often linked to MEN2A) and M918T (common in MEN2B). Loss-of-function RET mutations disrupt enteric nerve development and are a common cause of Hirschsprung disease, a condition characterized by absence of nerve cells in parts of the intestine.

Inheritance of RET mutations is typically autosomal dominant with variable penetrance and expressivity. Genetic testing is used to identify pathogenic RET variants in individuals with associated syndromes or a family history, guiding surveillance and management. In MEN2, risk-tailored strategies may include regular biochemical screening and, in carriers, prophylactic thyroidectomy at age- and mutation-dependent milestones to reduce medullary thyroid carcinoma risk. For RET-driven cancers, targeted therapies such as RET inhibitors (for example, selpercatinib and pralsetinib) have been approved for RET fusion-positive tumors; their role in germline RET-mutant syndromes is an active area of research, while surgical management remains central for MEN2-associated disease and Hirschsprung complications.

See also: MEN2, Hirschsprung disease, RET gene, RET inhibitors.