Congenital Central Hypoventilation Syndrome: A Novel Mutation of the RET Gene in an Isolated Case

Congenital Central Hypoventilation Syndrome:
A Novel Mutation of the RET Gene in an
Isolated Case

MASAYO KANAI, CHIKAHIKO NUMAKURA, AYAKO SASAKI, EMI SHIRAHATA,
KAZUHIRO AKABA, MOTOYA HASHIMOTO,¹ HISAYA HASEGAWA,² SENJI SHIRASAWA³
and KIYOSHI HAYASAKA

Department of Pediatrics, Yamagata University School of Medicine, Yamagata 990-9585,
¹Department of Neonatal Intensive Care Unit, Saiseikai Yamagata Saisei Hospital, Yamagata 990-8545,
²Department of Neonatology, Matsudo City Hospital, Chiba 271-0092, and
³Department of Genetics, Medical Institute of Bioregulation, Kyusyu University, Fukuoka 812-8582

Recently, a few genetic abnormalities were identified in congenital central hypoventilation syndrome (CCHS or Ondine's curse). CCHS is often associated with other neurocristopathies, especially with Hirschsprung's disease (HSCR). Mutations of the genes involved in the receptor tyrosine kinase RET (REarranged during Transfection) (RET)-glial cell line-derived neurotrophic factor (GDNF) and/or endothelin 3 (EDN3)-endothelin receptor-B (EDNRB) signaling pathway have been found in some of HSCR patients. In this study, we analyzed candidates for HSCR, namely the RET, GDNF, EDN3 and EDNRB genes in three isolated CCHS patients to confirm the hypothesis that some CCHS patients have a common genetic abnormality with patients having HSCR or other neurocristopathies. We found a novel R114H mutation of the RET gene in one patient. The R114H mutation is unlikely to be a polymorphism and appears to be associated with CCHS. In addition, we also examined the HOX11L2 (RNX) gene, for which knock-out mice showed CCHS-like syndrome in these isolated CCHS patients and did not detected any mutation. Further cases should be analyzed for more candidates to clarify the pathophysiology of CCHS.

Keywords —— congenital central hypoventilation syndrome (CCHS or Ondine's curse); RET-GDNF signaling pathway; EDN3-EDNRB signaling pathway; HOX11L2 gene (RNX)

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Tohoku J. Exp. Med., 2002, 196, 241-246

Address for reprints: Kiyoshi Hayasaka, M.D., Department of Pediatrics, Yamagata University School of Medicine, 2-2-2, Iida-nishi, Yamagata 990-9585, Japan.

e-mail : hayasaka@med.id.yamagata-u.ac.jp