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Human Molecular Genetics Advance Access originally published online on October 25, 2005
Human Molecular Genetics 2005 14(23):3697-3708; doi:10.1093/hmg/ddi401
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction

Delphine Trochet1, Seok Jong Hong2, Jin Kyu Lim2, Jean-François Brunet3, Arnold Munnich1, Kwang-Soo Kim2, Stanislas Lyonnet1, Christo Goridis3 and Jeanne Amiel1,*

1Université Paris-Descartes, Faculté de Médecine; INSERM; AP-HP, Hôpital Necker-Enfants Malades, INSERM U-393, Paris, France, 2Molecular Neurobiology Laboratory, MRC 216, McLean Hospital, Harvard Medical School, Belmont, MA, USA and 3CNRS UMR 8542, Département de Biologie, Ecole Normale Supérieure, Paris, France

* To whom correspondence should be addressed at: Département de Génétique, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75743 Paris Cedex 15, France. Tel: +33 144495648; Fax: +33 144495150; Email: amiel{at}necker.fr

Received August 23, 2005; Accepted October 14, 2005

Heterozygous mutations of the PHOX2B gene account for a broad variety of disorders of the autonomic nervous system, either isolated or combined, including congenital central hypoventilation syndrome (CCHS), tumours of the sympathetic nervous system and Hirschsprung disease. In CCHS, the prevalent mutation is an expansion of a 20-alanine stretch ranging from +5 to +13 alanines, whereas frameshift and missense mutations are found occasionally. To determine the molecular basis of impaired PHOX2B function, we assayed the transactivation and DNA binding properties of wild-type and mutant PHOX2B proteins. Furthermore, we investigated aggregate formation by proteins with polyalanine tract expansions ranging from +5 to +13 alanines using immunofluorescence of transfected cells and gel filtration of in vitro translated proteins. We found that transactivation of the dopamine beta-hydroxylase promoter by PHOX2B proteins with frameshift and missense mutations was abolished or severely curtailed, as was in vitro DNA binding although the proteins localized to the nucleus. The transactivation potential of proteins with polyalanine tract expansions declined with increasing length of the polyalanine stretch, and DNA binding was affected for an expansion of +9 alanines and above. Cytoplasmic aggregation in transfected cells was only observed for the longest expansions, whereas even the short expansion mutants were prone to form multimers in vitro. Such a tendency to protein misfolding could explain loss of transactivation for alanine expansion mutations. However, additional mechanisms such as toxic gain-of-function may play a role in the pathogenic process.


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