1. ¹Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
2. ²Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
3. ³Department of Pediatric Surgery, the Central Hospital, Aichi Prefectural Colony, 713-8 Kamiya-cho, Kasugai, Japan

Correspondence: Dr M Takahashi, Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Tel: +81 52 744 2093; Fax: +81 52 744 2098; E-mail: mtakaha@med.nagoya-u.ac.jp

Received 22 October 2002; Revised 17 January 2003; Accepted 24 January 2003.

Abstract

Germline mutations in the RET proto-oncogene are responsible for the development of human hereditary diseases, including multiple endocrine neoplasia (MEN) type 2A and 2B, familial medullary thyroid carcinoma (FMTC), and Hirschsprung's disease (HSCR). It has been reported that some families developed both MEN 2A/FMTC and HSCR, in which a mutation in a cysteine residue at codon 609, 618, or 620 in the RET gene was present. Here we report a novel RET mutation detected in a Japanese family with medullary thyroid carcinoma and HSCR. A germline mutation in cysteine 611 of the RET gene was identified in this family, which introduced an amino-acid change from cysteine to serine. By biological and biochemical analyses of mutant RET proteins, we previously predicted the potentiality that amino-acid substitution for cysteine 611 as well as cysteines 609, 618, and 620 would promote the development of MEN 2A/FMTC and HSCR. This clinical case substantiates our suggestion for the mechanism of the development of both the diseases.