Human Molecular Genetics Advance Access published online on May 18, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh156
© 2004 by Oxford University Press
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Comparative and Developmental Genetics Section, MRC Human Genetics Unit, Edinburgh EH4 2XU, UK
* To whom correspondence should be addressed. E-mail: sally.cross{at}hgu.mrc.ac.uk.
Dilp1 is a semi-dominant mouse mutation that causes dilated pupils when heterozygous and is lethal when homozygous. We report here that it is caused by a point mutation that introduces a stop codon close to the start of the coding sequence of the paired-like homeobox transcription factor Phox2b. Mice carrying a targeted allele of Phox2b also have dilated pupils and the two alleles do not complement. Phox2b is necessary for the development of the autonomic nervous system and when absent one of the consequences is that all parasympathetic ganglia fail to form. Constriction of the pupil is a parasympathetic response mediated by the ciliary ganglion and we find that in Phox2b heterozygous mutants it is highly atrophic. The development of other parasympathetic and sympathetic ganglia appears to be largely unaffected indicating that the ciliary ganglion is exquisitely sensitive to a reduction in dose of this transcription factor. PHOX2B has been implicated in human disease. Mutations, principally leading to polyalanine expansions within the protein, have been found in patients with congenital central hypoventilation syndrome (CCHS), the cardinal feature of which is an inability to breathe unassisted when asleep. Additionally, some CCHS patients have ocular abnormalities, including pupillary defects, although they principally have constricted rather than dilated pupils. The apparent phenotypic differences observed between mice carrying a loss-of-function mutation of Phox2b and CCHS patients indicate that PHOX2B mutations found in CCHS patients, all of which can produce proteins with intact DNA-binding domains, are gain-of-function mutations that alter rather than abolish protein function.
Article
Haploinsufficiency for Phox2b in mice causes dilated pupils and atrophy of the ciliary ganglion: mechanistic insights into human congenital central hypoventilation syndrome
2 CNRS UMR 8542, Département de Biologie, Ecole Normale Supérieure, 75005, Paris, France
3 Department of Histopathology, Leeds General Infirmary, Leeds LS1 3EX,UK; Department of Ophthalmic Pathology, Royal Eye Hospital, Manchester M13 9WH, UK
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. M. Bosley, D. T. Oystreck, R. L. Robertson, A. a. Awad, K. Abu-Amero, and E. C. Engle Neurological features of congenital fibrosis of the extraocular muscles type 2 with mutations in PHOX2A Brain, September 1, 2006; 129(9): 2363 - 2374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W. Hart, J. E. Morgan, J. Schneider, K. West, L. McKie, S. Bhattacharya, I. J. Jackson, and S. H. Cross Cardiac malformations and midline skeletal defects in mice lacking filamin A Hum. Mol. Genet., August 15, 2006; 15(16): 2457 - 2467. [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 de Pontual, A Pelet, D Trochet, F Jaubert, Y Espinosa-Parrilla, A Munnich, J-F Brunet, C Goridis, J Feingold, S Lyonnet, et al. Mutations of the RET gene in isolated and syndromic Hirschsprung's disease in human disclose major and modifier alleles at a single locus J. Med. Genet., May 1, 2006; 43(5): 419 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Horiuchi, A. Sasaki, M. Osawa, K. Kijima, Y. Ino, R. Matoba, and K. Hayasaka Sensitive Detection of Polyalanine Expansions in PHOX2B by Polymerase Chain Reaction Using Bisulfite-Converted DNA J. Mol. Diagn., November 1, 2005; 7(5): 638 - 640. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Durand, S. Dauger, A. Pattyn, C. Gaultier, C. Goridis, and J. Gallego Sleep-disordered Breathing in Newborn Mice Heterozygous for the Transcription Factor Phox2b Am. J. Respir. Crit. Care Med., July 15, 2005; 172(2): 238 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Amiel, D. Trochet, M. Clement-Ziza, A. Munnich, and S. Lyonnet Polyalanine expansions in human Hum. Mol. Genet., October 1, 2004; 13(suppl_2): R235 - R243. [Abstract] [Full Text] [PDF]
|
|