In Vitro studies of non poly alanine PHOX2B mutations argue against a loss‐of‐function mechanism for congenital central hypoventilation |
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Authors: | Delphine Trochet Yves Mathieu Loïc de Pontual Ravi Savarirayan Arnold Munnich Jean‐Franois Brunet Stanislas Lyonnet Christo Goridis Jeanne Amiel |
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Institution: | 1. INSERM U781 et Département de Génétique, H?pital Necker‐Enfants Malades, Université Paris Descartes, Faculté de Médecine, Assistance Publique–H?pitaux de Paris (AP‐HP), Paris, France;2. Royal Children's Hospital Clinical Genetics Units, Parkville, Australia;3. CNRS UMR 8542, Département de Biologie, Ecole Normale Supérieure, Paris, France |
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Abstract: | A wide range of autonomic dysfunctions, i.e. Central Hypoventilation Syndromes, Hirschsprung disease and Tumours of the Sympathetic Nervous System have been ascribed to heterozygous PHOX2B mutations in man. The PHOX2B mutations reported include polyalanine expansions in a 20 alanines tract, missense, frameshift mutations and nonsense mutation. Some genotype/phenotype correlations have been drawn, but the molecular mechanism(s) underlying them remain(s) unclear. So far, loss‐of‐function, gain‐of‐function and dominant negative effects have been proposed as disease‐causing mechanisms for polyalanine expansions. Indeed, mutant with an expanded polyalanine tract result in decreased transactivation of known target genes and protein misfolding leading to oligomerisation in vitro for all expansions and to cytoplasmic protein aggregation for longer expansions. We extended the molecular studies to other non‐polyalanine expansion mutations and show that most PHOX2B protein mutants oligomerize even in the absence of the normal 20 alanines tract. Conversely, a premature stop codon mutation in a CHS patient leads to the production of an N‐terminally truncated protein by re‐initiation of translation that does not form oligomers. Therefore, PHOX2B misfolding is not the only mechanism leading to dysfunction of the ventilatory autonomic system. © 2008 Wiley‐Liss, Inc. |
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Keywords: | PHOX2B CCHS protein misfolding dysautonomia |
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