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Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A
L M Mulligan1, J B Kwok, C S Healey
1Department of Pathology, University of Cambridge, UK.
Abstract:
Multiple endocrine neoplasia type 2A (MEN 2A) is a dominantly inherited cancer syndrome that affects tissues derived from neural ectoderm. It is characterized by medullary thyroid carcinoma (MTC) and phaeochromocytoma. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10q11.2 (refs 2,3). The DNA segment encompasses the RET proto-oncogene, a receptor tyrosine kinase gene expressed in MTC and phaeochromocytoma and at lower levels in normal human thyroid. This suggested RET as a candidate for the MEN2A gene. We have identified missense mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls. Further, 19 of these 20 mutations affect the same conserved cysteine residue at the boundary of the RET extracellular and transmembrane domains.
Insights
Multiple endocrine neoplasia type 2A (MEN 2A) is linked to mutations in the RET proto-oncogene. Most MEN 2A families studied showed specific RET gene mutations, implicating it in this inherited cancer syndrome.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Multiple endocrine neoplasia type 2A (MEN 2A) is an inherited cancer syndrome.
- MEN 2A is characterized by medullary thyroid carcinoma and phaeochromocytoma.
- The genetic basis for MEN 2A was recently localized to chromosome 10q11.2.
Purpose of the Study:
- To investigate the role of the RET proto-oncogene in MEN 2A.
- To identify mutations in the candidate MEN2A gene.
Main Methods:
- Genetic and physical mapping techniques were used to localize the MEN2A gene.
- DNA analysis was performed on MEN 2A families and normal controls.
- Missense mutations in the RET proto-oncogene were identified.
Main Results:
- The RET proto-oncogene was localized to the 480-kilobase region on chromosome 10q11.2 associated with MEN 2A.
- Missense mutations in the RET proto-oncogene were found in 20 out of 23 MEN 2A families.
- No RET mutations were observed in 23 normal controls.
- Nineteen of the 20 identified mutations affected a conserved cysteine residue in the RET gene.
Conclusions:
- The RET proto-oncogene is implicated as the MEN2A gene.
- Mutations in the RET proto-oncogene are a cause of MEN 2A.
- Specific mutations affecting the cysteine residue are strongly associated with MEN 2A.