Human Molecular Genetics Advance Access published online on May 11, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi188
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1 Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Genova, Italy
* To whom correspondence should be addressed. 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, D
Received February 23, 2005
Revised April 18, 2005
Accepted May 5, 2005
Article
Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in Congenital Central Hypoventilation Syndrome
2 Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Genova, Italy; Laboratorio di Fisiopatologia dell'Uremia, Istituto G. Gaslini, Genova, Italy
3 Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Genova, Italy; Dipartimento di Pediatria e CEBR, Università di Genova, Italy
Isabella Ceccherini, E-mail: isa.c{at}unige.it
Abstract 
H 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, while reduced transactivation due to polyalanine expansions may be caused by retention of the mutated protein in the cytoplasm or in nuclear aggregates, frameshift mutations did not impair the PHOX2B nuclear income, suggesting a different mechanism throught 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.
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