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Mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A (Sipple's syndrome)
S Oishi1, T Sato, S Takiguchi-Shirahama
1Third Department of Internal Medicine, Kumamoto University School of Medicine, Japan.
Abstract:
Genetic linkage analyses have traced the loci for multiple endocrine neoplasia type 2A (MEN 2A) to an interval on chromosome 10q11.2. This region encompasses the RET proto-oncogene, a receptor tyrosine kinase gene expressed in medullary thyroid carcinoma (MTC) and pheochromocytoma. By means of genomic polymerase chain reaction (PCR) amplification and DNA sequencing, we have analysed 19 individuals from two Japanese MEN 2A families for mutations of the RET proto-oncogene in exons 10 and 11. We conducted single-strand conformational polymorphism (SSCP) analysis of the RET proto-oncogene amplified from affected and unaffected family members. The DNA alterations in the RET proto-oncogene caused substitution of a cysteine for a serine at codon 620 in the exon 10 in three patients in one MEN 2A family, 1, and of a cysteine for a tyrosine at codon 634 in the exon 11 in six patients in the MEN 2A family, 2. We could find two asymptomatic MEN2A gene carriers who had no symptoms or signs of MEN 2A by DNA analysis of the RET proto-oncogene. No mutations in these exons were detected in any unaffected normal members of MEN 2A. A DNA alteration in the RET proto-oncogene coding sequence in exon 10 caused a shift on SSCP gels that was characteristic of the disease chromosome in the MEN 2A family, present only in affected members of the family. The DNA change could also be detected by restriction enzyme digestion with RsaI in family 2. Two MEN 2A patients with a cysteine for a tyrosine substitution at codon 634 in the exon 11 had parathyroid hyperplasia. We conclude that the identification of a DNA alteration in the MEN2A gene will permit predictive molecular testing of individuals at risk in these MEN 2A families and the PCR-restriction enzyme system will be useful for genetic diagnosis of members of these MEN 2A families. This information, by providing diagnostic certainty, should improve medical care for affected family members.
Insights
Genetic analysis identified RET proto-oncogene mutations in Japanese families with Multiple Endocrine Neoplasia type 2A (MEN 2A). These findings enable predictive molecular testing for at-risk individuals, improving patient care.
Area of Science:
- Human Genetics
- Oncology
- Molecular Biology
Background:
- Multiple Endocrine Neoplasia type 2A (MEN 2A) is a hereditary condition linked to chromosome 10q11.2.
- The RET proto-oncogene, a receptor tyrosine kinase, is implicated in MEN 2A pathogenesis and expressed in associated tumors.
- Previous studies localized MEN 2A loci to chromosome 10q11.2, a region containing the RET proto-oncogene.
Observation:
- Genetic linkage analyses pinpointed MEN 2A loci to chromosome 10q11.2, encompassing the RET proto-oncogene.
- Genomic PCR amplification and DNA sequencing were used to analyze 19 individuals from two Japanese MEN 2A families.
- Single-strand conformational polymorphism (SSCP) analysis identified specific RET proto-oncogene mutations in affected family members.
Findings:
- Specific RET proto-oncogene mutations were identified: cysteine-to-serine at codon 620 (exon 10) in three patients and cysteine-to-tyrosine at codon 634 (exon 11) in six patients.
- Two asymptomatic carriers of the MEN 2A gene were identified through DNA analysis.
- No RET proto-oncogene mutations in exons 10 and 11 were found in unaffected family members.
Implications:
- Identification of RET proto-oncogene DNA alterations allows for predictive molecular testing in at-risk individuals within these MEN 2A families.
- PCR-restriction enzyme systems offer a valuable tool for genetic diagnosis of MEN 2A family members.
- Diagnostic certainty derived from molecular testing can significantly improve medical care for individuals affected by MEN 2A.