Congenital Central Hypoventilation Syndrome (CCHS, MIM 209880), a very rare neonatal neurocristopathy sustained by defective migration and/or differentiation of neural crest derivatives, is characterized by abnormal ventilatory response to hypoxia and hypercapnia, owing to failure of autonomic respiratory control; affected children show an adequate ventilation while are awake but hypoventilate during sleep. Frameshift mutations (5%) and polyalanine triplet expansions (95%) have been detected in the coding region of the paired-like homeobox gene PHOX2B in about 90% of CCHS patients. A correlation between length of the expanded tracts and both severity of the respiratory phenotype and age at onset has been reported. CCHS is a lifelong disorder, and no pharmacological respiratory stimulants have turned out to be effective. The ventilatory supports such as tracheotomy, nasal mask, or diaphragm pacing by phrenic nerve stimulation represent the only options available in CCHS. Very recently it has been fortuitously observed that two females patients, using the progestin Desogestrel, for contraceptive purposes, dramatically ameliorated the clinical symptoms of CCHS, showing chemosensitivity recovery. However, the molecular mechanism of this pharmacological effect is completely unknown. The importance to understand the molecular mechanisms underlying the chemosensitivity recovery observed after desogestrel assumption relies on the necessity to identify potential pharmacological targets for alternative molecules without contraceptive effects, to be administered chronically also to male patients. Here we show that Desogestrel enhanced the expression of some relevant PHOX2B target genes in a promoter specific manner, by acting on the activity of the wild type as well as mutant protein.
THE PROGESTIN DESOGESTREL AUGMENTS PHOX2B TRANSCRIPTIONAL ACTIVITY: NEW THERAPEUTICAL APPROACHES IN CONGENITAL CENTRAL HYPOVENTILATION SYNDROME (CCHS)
R Benfante;
2014
Abstract
Congenital Central Hypoventilation Syndrome (CCHS, MIM 209880), a very rare neonatal neurocristopathy sustained by defective migration and/or differentiation of neural crest derivatives, is characterized by abnormal ventilatory response to hypoxia and hypercapnia, owing to failure of autonomic respiratory control; affected children show an adequate ventilation while are awake but hypoventilate during sleep. Frameshift mutations (5%) and polyalanine triplet expansions (95%) have been detected in the coding region of the paired-like homeobox gene PHOX2B in about 90% of CCHS patients. A correlation between length of the expanded tracts and both severity of the respiratory phenotype and age at onset has been reported. CCHS is a lifelong disorder, and no pharmacological respiratory stimulants have turned out to be effective. The ventilatory supports such as tracheotomy, nasal mask, or diaphragm pacing by phrenic nerve stimulation represent the only options available in CCHS. Very recently it has been fortuitously observed that two females patients, using the progestin Desogestrel, for contraceptive purposes, dramatically ameliorated the clinical symptoms of CCHS, showing chemosensitivity recovery. However, the molecular mechanism of this pharmacological effect is completely unknown. The importance to understand the molecular mechanisms underlying the chemosensitivity recovery observed after desogestrel assumption relies on the necessity to identify potential pharmacological targets for alternative molecules without contraceptive effects, to be administered chronically also to male patients. Here we show that Desogestrel enhanced the expression of some relevant PHOX2B target genes in a promoter specific manner, by acting on the activity of the wild type as well as mutant protein.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
