Human Molecular Genetics Advance Access originally published online on May 11, 2005
Human Molecular Genetics 2005 14(13):1815-1824; doi:10.1093/hmg/ddi188
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome
1Laboratorio di Genetica Molecolare and 2Laboratorio di Fisiopatologia dell'Uremia, Istituto Giannina Gaslini, Genova, Italy and 3Dipartimento di Pediatria e CEBR, Università di Genova, Genova, Italy
* To whom correspondence should be addressed at: Laboratorio Genetica Molecolare, Istituto Giannina Gaslini, L.go Gerolamo Gaslini 5, 16148 Genova, Italy. Tel: +39 105636800; Fax: +39 103779797; Email: isa.c{at}unige.it
Received February 23, 2005; Revised April 18, 2005; Accepted May 5, 2005
Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy characterized by absence of adequate autonomic control of respiration with decreased sensitivity to hypoxia and hypercapnia. Frameshift mutations and polyalanine triplet expansions in the coding region of PHOX2B have been identified in the vast majority of CCHS patients and a correlation between length of the expanded region and severity of CCHS has been reported. In this work, we have undertaken in vitro analyses aimed at identifying the pathogenetic mechanisms which underlie the effects of PHOX2B mutations in CCHS. According to the known role of this gene, a transcription factor expressed during autonomic nervous system development, we have tested the transcriptional activity of WT and mutant PHOX2B expression constructs on the regulatory regions of two target genes, DßH and PHOX2A. We observed that the two sets of mutations play different roles in the transcriptional regulation of these genes, showing a correlation between the length of polyalanine expansions and the severity of reduced transcriptional activity. In particular, although reduced transactivation due to polyalanine expansions may be caused by retention of the mutated protein in the cytoplasm or in the nuclear aggregates, frameshift mutations did not impair the PHOX2B nuclear income, suggesting a different mechanism through which they would exert the observed effects on target promoters. Moreover, the frameshift due to deletion of a cytosine residue seems to cause sequestration of the corresponding mutant PHOX2B in the nucleolar compartment.
Present address: Mouse Embryology Section, Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. J. Barkovich, K. J. Millen, and W. B. Dobyns A developmental and genetic classification for midbrain-hindbrain malformations Brain, November 20, 2009; (2009) awp247v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Dubreuil, J. Barhanin, C. Goridis, and J.-F. Brunet Breathing with Phox2b Phil Trans R Soc B, September 12, 2009; 364(1529): 2477 - 2483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Khan, H. B. Sarnat, and R. Spaetgens Congenital Muscle Fiber-Type Disproportion in a Patient With Congenital Central Hypoventilation Syndrome Due to PHOX2B Mutations J Child Neurol, July 1, 2008; 23(7): 829 - 831. [Abstract] [PDF]
|
|
|
|
 |
|
 D. Trochet, L. de Pontual, C. Straus, D. Gozal, H. Trang, P. Landrieu, A. Munnich, S. Lyonnet, C. Gaultier, and J. Amiel PHOX2B Germline and Somatic Mutations in Late-Onset Central Hypoventilation Syndrome Am. J. Respir. Crit. Care Med., April 15, 2008; 177(8): 906 - 911. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Moumne, A. Dipietromaria, F. Batista, A. Kocer, M. Fellous, E. Pailhoux, and R. A. Veitia Differential aggregation and functional impairment induced by polyalanine expansions in FOXL2, a transcription factor involved in cranio-facial and ovarian development Hum. Mol. Genet., April 1, 2008; 17(7): 1010 - 1019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Berry-Kravis, L. Zhou, C. M. Rand, and D. E. Weese-Mayer Congenital Central Hypoventilation Syndrome: PHOX2B Mutations and Phenotype Am. J. Respir. Crit. Care Med., November 15, 2006; 174(10): 1139 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A. Antic, B. A. Malow, N. Lange, R. D. McEvoy, A. L. Olson, P. Turkington, W. Windisch, M. Samuels, C. A. Stevens, E. M. Berry-Kravis, et al. PHOX2B Mutation-confirmed Congenital Central Hypoventilation Syndrome: Presentation in Adulthood Am. J. Respir. Crit. Care Med., October 15, 2006; 174(8): 923 - 927. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Bachetti, A. Robbiano, S. Parodi, I. Matera, E. Merello, V. Capra, M. P. Baglietto, A. Rossi, I. Ceccherini, and G. Ottonello Brainstem Anomalies in Two Patients Affected by Congenital Central Hypoventilation Syndrome Am. J. Respir. Crit. Care Med., September 15, 2006; 174(6): 706 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ramanantsoa, V. Vaubourg, S. Dauger, B. Matrot, G. Vardon, Z. Chettouh, C. Gaultier, C. Goridis, and J. Gallego Ventilatory response to hyperoxia in newborn mice heterozygous for the transcription factor Phox2b Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2006; 290(6): R1691 - R1696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Moumne, M. Fellous, and R. A. Veitia Deletions in the polyAlanine-containing transcription factor FOXL2 lead to intranuclear aggregation Hum. Mol. Genet., December 1, 2005; 14(23): 3557 - 3564. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Trochet, S. J. Hong, J. K. Lim, J.-F. Brunet, A. Munnich, K.-S. Kim, S. Lyonnet, C. Goridis, and J. Amiel Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction Hum. Mol. Genet., December 1, 2005; 14(23): 3697 - 3708. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Cargnin, A. Flora, S. D. Lascio, E. Battaglioli, R. Longhi, F. Clementi, and D. Fornasari PHOX2B Regulates Its Own Expression by a Transcriptional Auto-regulatory Mechanism J. Biol. Chem., November 11, 2005; 280(45): 37439 - 37448. [Abstract] [Full Text] [PDF]
|
|