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Molecular analysis of congenital central hypoventilation syndrome

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Abstract

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.

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References

  • Amiel J, Attie T, Simeoni J, Edery P, Gaultier C, Munnich A, Lyonnet S (1995) Mutation of the RET proto-oncogene in a patient with congenital central hypoventilation syndrome (Ondine’s curse) and Hirschsprung disease. Am J Hum Genet 57:A205

    Google Scholar 

  • Amiel J, Salmon R, Attie T, Pelet A, Trang H, Mokhtari M, Gaultie C, Munnich A, Lyonnet S (1998) Mutations of the RET-GDNF signaling pathway in Ondine’s curse. Am J Hum Genet 62:715–717

    Article  CAS  PubMed  Google Scholar 

  • Amiel J, Laudier B, Attie-Bitach T, Trang H, Pontual L de, Gener B, Trochet D, Etchevers H, Ray P, Simonneau M, Vekemans M, Munnich A, Gaultier C, Lyonnet S (2003) Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet 33:459–460

    Article  CAS  PubMed  Google Scholar 

  • Balkowiec A, Katz DM (1998) Brain-derived neurotrophic factor is required for normal development of the central respiratory rhythm in mice. J Physiol (Lond) 510:527–533

    Google Scholar 

  • Ball DW, Azzoli CG, Baylin SB, Chi D, Dou S, Donis-Keller H, Cumaraswamy A, Borges M, Nelkin BD (1993) Identification of a human achaete-scute homolog highly expressed in neuroendocrine tumors. Proc Natl Acad Sci USA 90:5648–5652

    CAS  PubMed  Google Scholar 

  • Bolk S, Angrist M, Xie J, Yanagisawa M, Silvestr JM, Weese-Mayer DE, Chakravarti A (1996) Endothelin-3 frameshift mutation in congenital central hypoventilation syndrome. Nat Genet 13:395–396

    CAS  PubMed  Google Scholar 

  • Brunet J-F, Pattyn A (2002) Phox2 genes—from patterning to connectivity. Curr Opin Genet Dev 12:435–440

    Article  CAS  PubMed  Google Scholar 

  • Burton MD, Kawashima A, Brayer JA, Kazemi H, Shannon DC, Schuchardt A, Costantini F, Pachnis V, Kinane TB (1997) RET proto-oncogene is important for the development of respiratory CO2 sensitivity. J Auton Nerv Syst 63:137–143

    Article  CAS  PubMed  Google Scholar 

  • Dauger S, Renolleau S, Vardon G, Nepote V, Mas C, Simonneau M, Gaultier C, Gallego J (1999) Ventilatory responses to hypercapnia and hypoxia in Mash-1 heterozygous newborn and adult mice. Pediatr Res 46: 535-542

    CAS  PubMed  Google Scholar 

  • Fitze G, Paditz E, Schlafke M, Kuhlisch E, Roesner D, Schackert HK (2003) Association of germline mutations and polymorphisms of the RET proto-oncogene with idiopathic congenital central hypoventilation syndrome in 33 patients. J Med Genet 40:E10

    Article  CAS  PubMed  Google Scholar 

  • Gozal D (1998) Congenital central hypoventilation syndrome: an update. Pediatr Pulmonol 26:276–282

    Article  Google Scholar 

  • Gozal D, Harper RM (1999) Novel insights into congenital hypoventilation syndrome. Curr Opin Pulm Med 5:335–338

    Article  CAS  PubMed  Google Scholar 

  • Haddad GG, Mazza NM, Defendini R, Blanc WA, Driscoll JM, Epstein MAF, Epstein, RA, Mellons RB (1978) Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine 57:517–526

    CAS  PubMed  Google Scholar 

  • Hamilton J, Bodurtha JN (1989) Congenital central hypoventilation syndrome and Hirschsprung’s disease in half sibs. J Med Genet 26:272–274

    CAS  PubMed  Google Scholar 

  • Kanai M, Numakura C, Sasaki A, Shirahata E, Akaba K, Hashimoto M, Hasegawa H, Shirakawa S, Hayasaka K (2002) Congenital central hypoventilation syndrome: a novel mutation of the RET gene in an isolated case. Tohoku J Exp Med 196:241–246

    CAS  PubMed  Google Scholar 

  • Kerbl R, Litscher H, Grubbauer HM, Reiterer F, Zobel G, Trop M, Urlesberger B, Eber E, Kurz R (1996) Congenital central hypoventilation syndrome (Ondine’s curse syndrome) in two siblings: delayed diagnosis and successful noninvasive treatment. Eur J Pedatr 155:977–980

    CAS  Google Scholar 

  • Khalifa MM, Flavin MA, Wherrett BA (1988) Congenital central hypoventilation syndrome in monozygotic twins. J Pediatr 113:853–855

    CAS  PubMed  Google Scholar 

  • Kuwaki T, Cao WH, Kurihara Y, Kurihara H, Ling GY, Onodera M, Ju KH, Yazaki Y, Kumada M (1996) Impaired ventilatory responses to hypoxia and hypercapnia in mutant mice deficient in endothelin-1. Am J Physiol 270:R1279–1286

    CAS  PubMed  Google Scholar 

  • Nakamura A, Kuwaki T, Kuriyama T, Yanagisawa M, Fukuda Y (2000) Normal ventilation and ventilatory responses to chemical stimuli in juvenile mutant mice deficient in endothelin-3. Respir Physiol 124:1–9

    Article  CAS  Google Scholar 

  • Nakano M, Yamada K, Fain J, Sener EC, Selleck CJ, Awad AH, Zwaan J, Mullaney PB, Bosley TM, Engle EC (2001) Homozygous mutations in ARIX (PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet 29:315–320

    Article  CAS  PubMed  Google Scholar 

  • Ohuchi T, Kuwaki T, Ling GY, Dewit D, Ju KH, Onodera M, Cao WH, Yanagisawa M, Kumada M (1999) Elevation of blood pressure by genetic and pharmacological disruption of the ETB receptor in mice. Am J Physiol 276:R1071–R1077

    CAS  PubMed  Google Scholar 

  • Pasini B, Borrello MG, Greco A, Bongarzone I, Luo Y, Mondellini P, Alberti L, Miranda C, Arighi E, Bocciardi R, Seri M, Barone V, Radice MT, Romeo G, Pierotti MA (1995) Loss of function effect of RET mutations causing Hirschsprung disease. Nat Genet 10:35–40

    CAS  PubMed  Google Scholar 

  • Pattyn A, Morin X, Cremer H, Goridis C, Brunet J-F (1999) The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Nature 399:366–370

    Article  CAS  PubMed  Google Scholar 

  • Sakai T, Wakizaka A, Matsuda H, Nirasawa Y, Itoh Y (1998) Point mutation on exon 12 of the receptor tyrosine kinase proto-oncogene RET in Ondine-Hirschsprung syndrome. Pediatrics 101:924–926

    CAS  PubMed  Google Scholar 

  • Shirasawa S, Arata A, Onimaru H, Roth KA, Brown GA, Horning S, Arata S, Okumura K, Sasazuki T, Korsmeyer SJ (2000) Rnx deficiency results in congenital central hypoventilation. Nat Genet 24:287–290

    Article  CAS  PubMed  Google Scholar 

  • Silvestri JM, Chen ML, Weese-Mayer DE, McQuitty JM, Carveth HJ, Nielson DWF, Teague WG (2002) Idiopathic congenital central hypoventilation syndrome: the next generation. Am J Med Genet 112:46–50

    Article  PubMed  Google Scholar 

  • Sritippayawan S, Harmutcu R, Kun SS, Ner Z, Ponce M, Keens TG (2002) Mother-daughter transmission of congenital central hypoventilation syndrome. Am J Respir Crit Care Med 166:367–369

    Article  PubMed  Google Scholar 

  • Stovroff M, Dykes F, Teague WG (1995) The complete spectrum of neurocristopathy in an infant with congenital hypoventilation, Hirschsprung’s disease and neuroblastoma. J Pediatr Surg 30:1218–1221

    CAS  PubMed  Google Scholar 

  • Swamininathan S, Gilsanz V, Atkinson J, Keens TG (1989) Congenital central hypoventilation syndrome associated with multiple ganglioneuromas. Chest 96:423–424

    PubMed  Google Scholar 

  • Verloes A, Elmer C, Lacombe D, Heinrichs C, Rebuffat E, Demarquez JL, Moncla A, Adam E (1993) Ondine-Hirschsprung syndrome (Haddad syndrome). Eur J Pediatr 152:75–77

    CAS  PubMed  Google Scholar 

  • Weese-Mayer DE, Silvestri JM, Menzies LJ, Morrow-Kenny AS, Hunt CE, Hauptman SA (1992) Congenital central hypoventilation syndrome: diagnosis, management, and long-term outcome in thirty-two children. J Pediatr 120:381–387

    CAS  PubMed  Google Scholar 

  • Weese-Mayer DE, Silvestri JM, Marazita ML, Hoo JJ (1993) Congenital central hypoventilation syndrome: inheritance and relation to sudden infant death syndrome. Am J Med Genet 47:360–367

    CAS  PubMed  Google Scholar 

  • Weese-Mayer DE, Shannon DC, Keens TG, Silvestri JM (1999) Idiopathic congenital central hypoventilation syndrome: diagnosis and management. Am J Resp Crit Care Med 160:368–373

    PubMed  Google Scholar 

  • Weese-Mayer DE, Bolk S, Silvestri JM, Chakravarti A (2002) Idiopathic congenital central hypoventilation syndrome: evaluation of brain-derived neurotrophic factor genomic DNA sequence variation. Am J Med Genet 107:306–310

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Prof. Y. Matsubara for helpful comments and discussions.

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Correspondence to Kiyoshi Hayasaka.

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Sasaki, A., Kanai, M., Kijima, K. et al. Molecular analysis of congenital central hypoventilation syndrome. Hum Genet 114, 22–26 (2003). https://doi.org/10.1007/s00439-003-1036-z

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  • DOI: https://doi.org/10.1007/s00439-003-1036-z

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