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Parental origin and somatic mosaicism of PHOX2B mutations in Congenital Central Hypoventilation Syndrome

✍ Scribed by Sara Parodi; Tiziana Bachetti; Francesca Lantieri; Marco Di Duca; Giuseppe Santamaria; Giancarlo Ottonello; Ivana Matera; Roberto Ravazzolo; Isabella Ceccherini

Publisher: John Wiley and Sons
Year: 2007
Tongue: English
Weight: 191 KB
Volume: 29
Category: Article
ISSN: 1059-7794
DOI: 10.1002/humu.9516

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✦ Synopsis

Communicated by Michel Goossens

Heterozygous polyalanine repeat expansions of PHOX2B have been associated with Congenital Central Hypoventilation Syndrome, a rare neurocristopathy characterized by absence of adequate control of respiration during sleep. Here we report a PHOX2B mutational screening in 63 CCHS patients, 58 of whom presenting with poly-A expansions or frameshift, missense and nonsense mutations. To assess a somatic or germline occurrence of poly-A length variations, the relative amounts of mutant and wild type alleles have been quantified in 20 selected CCHS patients presenting with an expansion, and in their parents. Somatic mosaicism was shown in four parents, while no mosaic was found among CCHS patients. Moreover, while co-segregation analysis of the PHOX2B poly-A expansions with selected marker alleles in the same 20 CCHS trios has not demonstrated any parent-oforigin effect of the mutations, it has provided further clues to clarify the molecular mechanism underlying the expansion occurrence. Finally, the segregation of PHOX2B poly-A anomalous tracts within family members has allowed us to exclude tendency of polymorphic variations towards expansion. This strengthens the notion that expanded polyalanine tracts, identified as frequent disease-causing mutations also in other human diseases, are mitotically and meiotically stable.

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