Identification of a new Jnk-activating familial SOS1 and a de novo RAF1 mutations in a Noonan syndrome patient
Abstract
Data di Pubblicazione:
2010
Citazione:
Identification of a new Jnk-activating familial SOS1 and a de novo RAF1 mutations in a Noonan syndrome patient / M. Longoni, S. Moncini, M. Cisternino, I. Morella, S. Ferraiuolo, S. Russo, P. Coi, R. Zippel, M. Venturin, P. Riva. - In: EUROPEAN JOURNAL OF HUMAN GENETICS. - ISSN 1018-4813. - 18:Suppl.1(2010), pp. 333-333. ((Intervento presentato al convegno European Human Genetics Conference tenutosi a Gothenburg nel 2010.
Abstract:
Noonan syndrome is an autosomal dominant genetic disease characterized
by congenital heart defects, short stature and characteristic
facial features. Mutations in PTPN11, RAF1, SOS1, KRAS, and NRAS
are responsible for 60-75% of the cases, thus additional genes, are expected
to be involved in Noonan syndrome pathogenesis. The genotype/
phenotype correlation has been hindered by the relatively few reported
genotyped cases. Expanding the case numbers will benefit the
clinical community. A mutation analysis has been performed on RAF1,
SOS1 and on the SOS1-interacting GRB2, in twenty-four NS patients
previously found to be negative for PTPN11 and KRAS mutations. We
identified four mutations in SOS1 and one in RAF1, while no GRB2
variants have been found. Interestingly the RAF1 mutation was present
in a patient also carrying a newly identified p.R497Q familial SOS1
mutation, segregating with a typical NS SOS1 cutaneous phenotype.
The new SOS1 mutations have been predicted to dysregulate the protein
activity by bioinformatics. Functional analysis demonstrated the
R497Q-SOS1 mutation leads to Jnk activation, but had no effect on
the Ras effector Erk1. We propose that this variant might contribute
to the onset of the peculiar ectodermal traits displayed by the proband
amidst the more classical NS presentation. The characteristic cutaneous
traits, frequently shown by NS patients carrying SOS1 mutations,
might be associated to the activation of both Jnk/Erk pathways. To our
knowledge, this is the first reported case of a NS patient harbouring
mutations in two NS genes, allowing us to propose a genotype/phenotype
correlation in the family
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
M. Longoni, S. Moncini, M. Cisternino, I. Morella, S. Ferraiuolo, S. Russo, P. Coi, R. Zippel, M. Venturin, P. Riva
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