Molecular analysis of congenital central hypoventilation syndrome.
Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a disorder characterized by an idiopathic failure of the automatic control of breathing. CCHS is frequently complicated with neurocristopathies such as Hirschsprung's disease (HSCR). The genes involved in the RET-GDNF signaling and/or EDN3-EDNRB signaling pathways have been analyzed as candidates for CCHS; however, only a few patients have mutations of the RET, EDN3, and GDNF genes. Recently, mutations of the PHOX2B gene, especially polyalanine expansions, have been detected in two thirds of patients. We studied the RET, GDNF, GFRA1, PHOX2A, PHOX2B, HASH-1, EDN1, EDN3, EDNRB, and BDNF genes in seven patients with isolated CCHS and three patients with HSCR. We detected polyalanine expansions and a novel frameshift mutation of the PHOX2B gene in four patients and one patient, respectively. We also found several mutations of the RET, GFRA1, PHOX2A, and HASH-1 genes in patients with or without mutations of the PHOX2B gene. Our study confirmed the prominent role of mutations in the PHOX2B gene in the pathogenesis of CCHS. Mutations of the RET, GFRA1, PHOX2A, and HASH-1 genes may also be involved in the pathogenesis of CCHS. To make clear the pathogenesis of CCHS, the analysis of more cases and further candidates concerned with the development of the autonomic nervous system is required.
Sasaki
Ayako
A
Department of Pediatrics, Yamagata Univercity School of Medicine, 2-2-2 Iida-nishi, 990-9585 Yamagata, Japan.
Kanai
Masayo
M
Kijima
Kazuki
K
Akaba
Kazuhiro
K
Hashimoto
Motoya
M
Hasegawa
Hisaya
H
Otaki
Shinsuke
S
Koizumi
Takenobu
T
Kusuda
Satoshi
S
Ogawa
Youhei
Y
Tuchiya
Keiji
K
Yamamoto
Wakako
W
Nakamura
Tomohiko
T
Hayasaka
Kiyoshi
K
D017668:Age of Onset; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D007223:Infant; D008297:Male; D009414:Nerve Growth Factors / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D012121:Respiration, Artificial; D020182:Sleep Apnea, Central / Q000235:genetics*; D013577:Syndrome
C495039:GDNF protein, human; C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases