Studies of Multiple Endocrine Neoplasia Type 2A Syndrome: Linkage Analyses and Comparison of Constitutional and Tumor Genotypes

Linkage analyses were carried out in nine Japanese kindreds with multiple endocrine neoplasia type 2A (MEN-2A) using polymorphic classical markers and DNA markers. We excluded close linkage of the MEN-2A gene (MEN2A) locus with Gm, JK, PGMl, and a DNA segment, D20S5, which is assigned to band 12 of the short arm of chromosome 20 (20p12.2). Assuming that MEN2A is recessive at the cellular level as in retinoblastoma (RB) and Wilms\u27 tumor (WT). comparison of constitutional and tumor genotypes may be useful in the search for the MEN2A locus. When DNA samples from 12 patients with medullary thyroid carcinoma (MTC) were compared with 15 polymorphic DNA markers including two assigned to chromosome 20, the results were negative. Both the negative linkage data and the failure to find loss of heterozygosity in MTC with chromosome 20 probes suggest that MEN2A may not be at 20p12.2, which was previously suggested as the site of an inherited chromosomal deletion in MEN-2A

Dual assemblies of an activating immune receptor, MAIR-II, with ITAM-bearing adapters DAP12 and FcR gamma chain on peritoneal macrophages

Certain activating immune receptors expressed on myeloid cells noncovalently associate with either DAP12 or Fc epsilon RI gamma (FcR gamma chain), the ITAM-bearing transmembrane adapter proteins. An activating receptor, myeloid-associated Ig-like receptor (MAIR) II, is expressed on a subset of B cells and macrophages in the spleen and peritoneal cavity of mice and associates with DAP12 in these cells. However, we demonstrate here that cross-linking MAIR-II with mAb induced secretion of a significant amount of the inflammatory cytokines TNF-alpha and IL-6 from DAP12(-/-) as well as wild-type (WT) peritoneal macrophages. We show that MAIR-II associates with not only DAP12 but also FcR gamma chain homodimers in peritoneal macrophages. LPS enhanced the FcR gamma chain expression and FcR gamma chain-dependent cell surface expression of MAIR-II and had additive effects on MAIR-II-mediated inflammatory cytokine secretion from peritoneal macrophages. The lysine residue in the transmembrane region of MAIR-II was involved in the association with FcR-y chain as well as DAP12. Our findings present the first case of an activating receptor that uses either DAP12 or FcRC gamma chain as a signaling adapter. The FcR-y chain may provide cooperation with and/or compensation for DAP12 in MAIR-II-mediated inflammatory responses by peritoneal macrophages

The immunoreceptor adapter protein DAP12 suppresses B lymphocyte–driven adaptive immune responses

Human and mouse B cells lacking functional DAP12 are hyperresponsive, and DAP12 works with MAIR-II (CD300d) to negatively regulate B cell activity

Multiple Endocrine Neoplasia Type 2 Syndromes in Japan

Through nationwide surveys, we collected and analyzed 242 patients of medullary thyroid carcinoma (MTC). Included were 40 patients with multiple endocrine neoplasia type 2A (MEN-2A), six patients with MEN-2B, and 36 patients with only MTC having a positive family history (82 total patients in the hereditary group). Ten-year survival rates were 81.5% for all cases, and 97.5% and 76.1% for the hereditary and the sporadic group, respectively. Epinephrine/norepinephrine ratio in the urine was found to be a good indicator of the adrenomedullary hyperfunction in patients with hereditary MTC. At least one patient in each family with hereditary MTC had overt pheochromocytoma or latent hyperfunction of adrenal medulla. Doubling times of plasma calcitonin levels correlated with life expectancy and recurrence rates. We carried out linkage analysis between the MEN-2 locus and several genetic markers in our MEN-2 families, but so far we have been unable to demonstrate or exclude a linkage

Expression of the ret Proto-oncogene in Human Medullary Thyroid Carcinomas and Pheochromocytomas of MEN 2A

We studied the expression of the ret proto-oncogene (proto-ret) in human medullary thyroid carcinomas (MTCs) and pheochromocytomas of multiple endocrine neoplasia type 2A (MEN 2A) by Northern blot analysis. Expression of the normal-sized transcripts was detected in all 12 MTCs and in 6 of 8 pheochromocytomas. In situ localization of proto-ret mRNA revealed that the signal was confined to the cytoplasm of MTC cells. By Southern blot analysis neither amplification nor gross genetic changes of proto-ret were found in the tumors. Although no transcripts were detected in the normal portion of the thyroid from one MEN 2A patient,faint signals were detected in normal adrenal glands by Northern blot analysis, probably due to minor populations of C-cells and chromaffin cells in specimens from which MTC and pheochromocytoma might later develop. Proto-ret may play an important role in differentiation of a specific cell lineage from neuroectoderm, and it may be involved in development of MEN 2A tumors

Allele Loss on Chromosome 10 and Point Mutation of ras Oncogenes are Infrequent in Tumors of MEN 2 A

The multiple endocrine neoplasia type 2A (MEN 2A) gene has been mapped to the centromeric region of chromosome 10 by linkage analysis. We examined 36 medullary thyroid carcinomas (MTCs) (16 hereditary and 20 sporadic) and ten pheochromocytomas (eight hereditary and two sporadic) to detect loss of alleles on chromosome 10 using seven polymorphic DNA markers mapped to this chromosome. Of 20 informative cases, only one (5%) sporadic MTC showed loss of heterozygosity at the locus RBP3. Allele loss at the RBP3 locus was not found in pheochromocytomas from six heterozy gates. All tumors retained constitutional heterozygosity at six other loci on chromosome 10 (D10S17, D10S34, D10S24 on the short arm, D10S15 in the pericentromeric region, D10S20, and D10S4 on the long arm). Our findings suggest that the second hit for tumorigenesis in MEN 2 A may not be loss of function of the normal allele at the homologous locus on the other copy of chromosome 10. Mutated ras oncogene was found only in one of 18 MTCs at the codon 61 of H-ras