title: NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome.
abstract: Neurofibromatosis type 1 (NF1) demonstrates phenotypic overlap with Noonan syndrome (NS) in some patients, which results in the so-called neurofibromatosis-Noonan syndrome (NFNS). From a genetic point of view, NFNS is a poorly understood condition, and controversy remains as to whether it represents a variable manifestation of either NF1 or NS or is a distinct clinical entity. To answer this question, we screened a cohort with clinically well-characterized NFNS for mutations in the entire coding sequence of the NF1 and PTPN11 genes. Heterozygous NF1 defects were identified in 16 of the 17 unrelated subjects included in the study, which provides evidence that mutations in NF1 represent the major molecular event underlying this condition. Lesions included nonsense mutations, out-of-frame deletions, missense changes, small inframe deletions, and one large multiexon deletion. Remarkably, a high prevalence of inframe defects affecting exons 24 and 25, which encode a portion of the GAP-related domain of the protein, was observed. On the other hand, no defect in PTPN11 was observed, and no lesion affecting exons 11-27 of the NF1 gene was identified in 100 PTPN11 mutation-negative subjects with NS, which provides further evidence that NFNS and NS are genetically distinct disorders. These results support the view that NFNS represents a variant of NF1 and is caused by mutations of the NF1 gene, some of which have been demonstrated to cause classic NF1 in other individuals.
authors.affiliation: CSS Hospital, IRCCS, San Giovanni Rotondo and CSS-Mendel Institute, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: De Luca
authors.forename: Irene
authors.initials: I
authors.lastname: Bottillo
authors.forename: Anna
authors.initials: A
authors.lastname: Sarkozy
authors.forename: Claudio
authors.initials: C
authors.lastname: Carta
authors.forename: Cinzia
authors.initials: C
authors.lastname: Neri
authors.forename: Emanuele
authors.initials: E
authors.lastname: Bellacchio
authors.forename: Annalisa
authors.initials: A
authors.lastname: Schirinzi
authors.forename: Emanuela
authors.initials: E
authors.lastname: Conti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.forename: Agatino
authors.initials: A
authors.lastname: Battaglia
authors.forename: Silvia
authors.initials: S
authors.lastname: Majore
authors.forename: Maria M
authors.initials: MM
authors.lastname: Rinaldi
authors.forename: Massimo
authors.initials: M
authors.lastname: Carella
authors.forename: Bruno
authors.initials: B
authors.lastname: Marino
authors.forename: Antonio
authors.initials: A
authors.lastname: Pizzuti
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Digilio
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
mesh_terms: D002648:Child; D018389:Codon, Nonsense; D015331:Cohort Studies; D005091:Exons; D005260:Female; D016514:Genes, Neurofibromatosis 1; D005819:Genetic Markers; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008967:Molecular Biology; D008968:Molecular Conformation; D009154:Mutation; D009456:Neurofibromatosis 1 / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D025542:Neurofibromin 1 / Q000737:chemistry; D009634:Noonan Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D015995:Prevalence; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion
chemical_list: D018389:Codon, Nonsense; D005819:Genetic Markers; D025542:Neurofibromin 1