Rare somatic inactivation of the multiple endocrine neoplasia type 1 gene in secondary hyperparathyroidism of uremia

The molecular pathway of autonomous growth of the parathyroid glands in ure mic patients is poorly understood. Loss of heterozygosity at the recently i dentified multiple endocrine neoplasia type 1 (MEN1) gene locus on chromoso me 11q13 has been found in a subset of parathyroid glands from patients wit h refractory hyperparathyroidism. To clarify the role of the MEN1 gene in p arathyroid tumorigenesis, we analyzed 81 parathyroid glands from 22 Japanes e uremic patients for allelic loss on chromosomal arm 11q13 DNA using 3 fla nking markers (PYGM, D11S4946, and D11S449) and for mutations of the MEN1-c oding exons by PCR-based single strand conformation polymorphism analysis a nd sequencing. Allelic loss on 11q13 was observed in 6 glands (7%), and 1 o f 6 demonstrated a previously unrecognized somatic frameshift deletion (331 delG) of the MEN1 gene. This mutation would probably result in a nonfunctio nal menin protein, consistent with a tumor suppressor mechanism. Clinical a nd pathological characteristics of hyperparathyroidism were unrelated to th e presence or absence of loss of heterozygosity on 11q13 and MEN1 gene muta tions. These observations indicate that somatic inactivation of the MEN1 ge ne contributes to the pathogenesis of uremia-associated parathyroid tumors, but its role in this disease appears to be very limited.