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Updated: Aug 21, 2026
Generation of a Mouse Spontaneous Autoimmune Thyroiditis Model
Published on: March 17, 2023
A new germline RET mutation apparently devoid of transforming activity serendipitously discovered in a patient with
G Orgiana1, G Pinna, A Camedda
1Division of Endocrinology, University of Cagliari, 09042 Monserrato-Cagliari, Italy.
Abstract:
Gain-of-function RET mutations are responsible for multiple endocrine neoplasia syndromes (MEN) 2A and 2B and familial medullary thyroid carcinoma (FMTC), whereas loss-of-function mutations are found in Hirschsprung disease. We report a new RET point mutation [R694Q (CGG-->CAG)], serendipitously found in a 23-yr-old woman with hypothyroidism due to atrophic Hashimoto's thyroiditis and primary ovarian failure, without altered calcitonin secretion. Familial history and clinical and biochemical evaluation of first-degree relatives were negative for FMTC, MEN 2A and 2B, and Hirschsprung disease. Genetic analysis showed that the mutation was inherited from the mother, who was submitted 2 yr before to thyroidectomy for goitrous Hashimoto's thyroiditis. Histological revision and immunohistochemical studies documented normal C cell number and morphology. We cloned the mutation in an expression vector encoding a full-length RET protein. The construct was transiently expressed in 293T cells in parallel with a wild-type RET and a C634R MEN 2A-associated RET mutant. Proteins were harvested from transfected cells, and tyrosine phosphorylation levels were assayed. The mutation did not exert significant potentiating effects on RET kinase. A focus assay was also performed on NIH3T3 fibroblasts; the mutant did not exert significant transforming activity. In conclusion, a new RET mutation was found in two subjects without any evidence of MEN and FMTC. In keeping with clinical data, transfection studies confirmed lack of activating activity. This serendipitous discovery, apparently devoid of oncogenic potential, underscores the problems that may be encountered in genomic studies on RET.
Insights
A novel RET gene mutation, R694Q, was identified in individuals without Multiple Endocrine Neoplasia (MEN) or Familial Medullary Thyroid Carcinoma (FMTC). Functional studies confirmed this mutation lacks oncogenic activity, highlighting challenges in RET gene research.
Area of Science:
- Genetics
- Oncology
- Endocrinology
Background:
- Gain-of-function RET mutations cause MEN 2A/2B and FMTC.
- Loss-of-function RET mutations are linked to Hirschsprung disease.
- The RET proto-oncogene plays a critical role in neuroendocrine development and tumorigenesis.
Observation:
- A novel RET point mutation, R694Q, was incidentally discovered in a young woman with hypothyroidism and ovarian failure.
- The mutation was inherited from her mother, who had Hashimoto's thyroiditis but no history of MEN or FMTC.
- Extensive familial screening revealed no clinical or biochemical evidence of MEN syndromes or Hirschsprung disease.
Findings:
- In vitro studies demonstrated that the R694Q RET mutant exhibited no significant potentiation of RET kinase activity.
- Focus assays in NIH3T3 fibroblasts showed the R694Q mutant lacked significant transforming activity.
- These functional assays confirmed the lack of activating potential for the novel RET mutation.
Implications:
- This discovery identifies a new RET mutation in individuals without associated endocrine neoplasia syndromes.
- The findings underscore the complexity of RET mutations and their variable clinical penetrance.
- It highlights potential challenges in interpreting incidental genetic findings within the context of genomic screening programs.
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