Abstract
Noonan syndrome is a genetic condition characterized by congenital heart defects, short stature, and characteristic facial features. Familial or de novo 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 the pathogenesis. In addition, the genotype-phenotype correlation has been hindered by the highly variable expressivity of the disease. For all these reasons, expanding the genotyped and clinically evaluated case numbers will benefit the clinical community. A mutation analysis has been performed on RAF1, SOS1, and GRB2, in 24 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 Noonan Syndrome SOS1 cutaneous phenotype. Functional analysis demonstrated that the R497Q SOS1 mutation leads to Jnk activation, but has 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 propositus amidst the more classical Noonan syndrome presentation. To our knowledge, this is the first reported case of a patient harboring mutations in two genes, with an involvement of both Ras and Rac1 pathways, indicating that SOS1 may have a role of modifier gene that might contribute the variable expressivity of the disease, evidencing a genotype-phenotype correlation in the family.
| Original language | English |
|---|---|
| Pages (from-to) | 2176-2184 |
| Number of pages | 9 |
| Journal | American Journal of Medical Genetics, Part A |
| Volume | 152 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Sep 2010 |
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Keywords
- Genotype-phenotype correlation
- GRB2
- Jnk activation
- Mutational analysis
- Noonan syndrome
- RAF1
- SOS1
ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
Cite this
Noonan syndrome associated with both a new Jnk-activating familial SOS1 and a de novo RAF1 mutations. / Longoni, Mauro; Moncini, Silvia; Cisternino, Mariangela; Morella, Ilaria M.; Ferraiuolo, Serena; Russo, Silvia; Mannarino, Savina; Brazzelli, Valeria; Coi, Paola; Zippel, Renata; Venturin, Marco; Riva, Paola.
In: American Journal of Medical Genetics, Part A, Vol. 152, No. 9, 09.2010, p. 2176-2184.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Noonan syndrome associated with both a new Jnk-activating familial SOS1 and a de novo RAF1 mutations
AU - Longoni, Mauro
AU - Moncini, Silvia
AU - Cisternino, Mariangela
AU - Morella, Ilaria M.
AU - Ferraiuolo, Serena
AU - Russo, Silvia
AU - Mannarino, Savina
AU - Brazzelli, Valeria
AU - Coi, Paola
AU - Zippel, Renata
AU - Venturin, Marco
AU - Riva, Paola
PY - 2010/9
Y1 - 2010/9
N2 - Noonan syndrome is a genetic condition characterized by congenital heart defects, short stature, and characteristic facial features. Familial or de novo 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 the pathogenesis. In addition, the genotype-phenotype correlation has been hindered by the highly variable expressivity of the disease. For all these reasons, expanding the genotyped and clinically evaluated case numbers will benefit the clinical community. A mutation analysis has been performed on RAF1, SOS1, and GRB2, in 24 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 Noonan Syndrome SOS1 cutaneous phenotype. Functional analysis demonstrated that the R497Q SOS1 mutation leads to Jnk activation, but has 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 propositus amidst the more classical Noonan syndrome presentation. To our knowledge, this is the first reported case of a patient harboring mutations in two genes, with an involvement of both Ras and Rac1 pathways, indicating that SOS1 may have a role of modifier gene that might contribute the variable expressivity of the disease, evidencing a genotype-phenotype correlation in the family.
AB - Noonan syndrome is a genetic condition characterized by congenital heart defects, short stature, and characteristic facial features. Familial or de novo 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 the pathogenesis. In addition, the genotype-phenotype correlation has been hindered by the highly variable expressivity of the disease. For all these reasons, expanding the genotyped and clinically evaluated case numbers will benefit the clinical community. A mutation analysis has been performed on RAF1, SOS1, and GRB2, in 24 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 Noonan Syndrome SOS1 cutaneous phenotype. Functional analysis demonstrated that the R497Q SOS1 mutation leads to Jnk activation, but has 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 propositus amidst the more classical Noonan syndrome presentation. To our knowledge, this is the first reported case of a patient harboring mutations in two genes, with an involvement of both Ras and Rac1 pathways, indicating that SOS1 may have a role of modifier gene that might contribute the variable expressivity of the disease, evidencing a genotype-phenotype correlation in the family.
KW - Genotype-phenotype correlation
KW - GRB2
KW - Jnk activation
KW - Mutational analysis
KW - Noonan syndrome
KW - RAF1
KW - SOS1
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UR - http://www.scopus.com/inward/citedby.url?scp=77956099847&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.33564
DO - 10.1002/ajmg.a.33564
M3 - Article
C2 - 20683980
AN - SCOPUS:77956099847
VL - 152
SP - 2176
EP - 2184
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
SN - 1552-4825
IS - 9
ER -