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SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations.

Lepri F, De Luca A, Stella L, Rossi C, Baldassarre G, Pantaleoni F, Cordeddu V, Williams BJ, Dentici ML, Caputo V, Venanzi S, Bonaguro M, Kavamura I, Faienza MF, Pilotta A, Stanzial F, Faravelli F, Gabrielli O, Marino B, Neri G, Silengo MC, Ferrero GB, Torrrente I, Selicorni A, Mazzanti L, Digilio MC, Zampino G, Dallapiccola B, Gelb BD, Tartaglia M - Hum. Mutat. (2011)

Bottom Line: Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features.Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized.Genotype-phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth.

View Article: PubMed Central - PubMed

Affiliation: IRCCS Casa Sollievo della Sofferenza, Laboratorio Mendel, San Giovanni Rotondo, Italy.

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Related in: MedlinePlus

Facial dysmorphism and other features of subjects with Noonan syndrome heterozygous for mutations in the SOS1 gene. SOS1 mutation-positive subjects generally exhibit typical facial features, including macrocephaly, hypertelorism, ptosis, downslanting palpebral fissures, sparse eyebrows with keratosis pylaris, a short and broad nose with upturned tip, low-set and posteriorly angulated ears, and high forehead commonly associated with bitemporal narrowing and prominent supraorbital ridges. Curly hair is present in most of the patients. Other common features include pectus anomalies (NS10, NS19, NS37), short and/or webbed neck (NS6, NS10, NS19, NS22, NS38), and cubitus valgus (NS37). Keloid scars (NS16), recurrent hemorrhages (NS18), and deep plantar creases (NS38) also occur in these subjects. In some infants, the face is suggestive of cardiofaciocutaneous syndrome due to the coarseness of features (NS39).
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fig03: Facial dysmorphism and other features of subjects with Noonan syndrome heterozygous for mutations in the SOS1 gene. SOS1 mutation-positive subjects generally exhibit typical facial features, including macrocephaly, hypertelorism, ptosis, downslanting palpebral fissures, sparse eyebrows with keratosis pylaris, a short and broad nose with upturned tip, low-set and posteriorly angulated ears, and high forehead commonly associated with bitemporal narrowing and prominent supraorbital ridges. Curly hair is present in most of the patients. Other common features include pectus anomalies (NS10, NS19, NS37), short and/or webbed neck (NS6, NS10, NS19, NS22, NS38), and cubitus valgus (NS37). Keloid scars (NS16), recurrent hemorrhages (NS18), and deep plantar creases (NS38) also occur in these subjects. In some infants, the face is suggestive of cardiofaciocutaneous syndrome due to the coarseness of features (NS39).

Mentions: SOS1 mutation-positive subjects displayed typical facial features (Fig. 3). Macrocephaly was, however, overrepresented compared to the general NS population (61 vs. 12%) [Sharland et al., 1992]. Among these subjects, cardiac defects were frequently observed (89% of cases), with PS, ASD. and VSD being the most recurrent anomalies, while prevalence of HCM was comparable to that observed in PTPN11 mutation-associated NS, occurring in less than 10% of cases [Sarkozy et al., 2009b]. Of note, PS was found to be frequently associated with ASD (35% of cases). Finally, two subjects were documented to present with mandibular multiple giant cell lesions (MGCLs), which were associated with multiple tumors, including abdominal rhabdomyosarcoma, cerebral glioma, and skin granular cell tumors in one subject.


SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations.

Lepri F, De Luca A, Stella L, Rossi C, Baldassarre G, Pantaleoni F, Cordeddu V, Williams BJ, Dentici ML, Caputo V, Venanzi S, Bonaguro M, Kavamura I, Faienza MF, Pilotta A, Stanzial F, Faravelli F, Gabrielli O, Marino B, Neri G, Silengo MC, Ferrero GB, Torrrente I, Selicorni A, Mazzanti L, Digilio MC, Zampino G, Dallapiccola B, Gelb BD, Tartaglia M - Hum. Mutat. (2011)

Facial dysmorphism and other features of subjects with Noonan syndrome heterozygous for mutations in the SOS1 gene. SOS1 mutation-positive subjects generally exhibit typical facial features, including macrocephaly, hypertelorism, ptosis, downslanting palpebral fissures, sparse eyebrows with keratosis pylaris, a short and broad nose with upturned tip, low-set and posteriorly angulated ears, and high forehead commonly associated with bitemporal narrowing and prominent supraorbital ridges. Curly hair is present in most of the patients. Other common features include pectus anomalies (NS10, NS19, NS37), short and/or webbed neck (NS6, NS10, NS19, NS22, NS38), and cubitus valgus (NS37). Keloid scars (NS16), recurrent hemorrhages (NS18), and deep plantar creases (NS38) also occur in these subjects. In some infants, the face is suggestive of cardiofaciocutaneous syndrome due to the coarseness of features (NS39).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3118925&req=5

fig03: Facial dysmorphism and other features of subjects with Noonan syndrome heterozygous for mutations in the SOS1 gene. SOS1 mutation-positive subjects generally exhibit typical facial features, including macrocephaly, hypertelorism, ptosis, downslanting palpebral fissures, sparse eyebrows with keratosis pylaris, a short and broad nose with upturned tip, low-set and posteriorly angulated ears, and high forehead commonly associated with bitemporal narrowing and prominent supraorbital ridges. Curly hair is present in most of the patients. Other common features include pectus anomalies (NS10, NS19, NS37), short and/or webbed neck (NS6, NS10, NS19, NS22, NS38), and cubitus valgus (NS37). Keloid scars (NS16), recurrent hemorrhages (NS18), and deep plantar creases (NS38) also occur in these subjects. In some infants, the face is suggestive of cardiofaciocutaneous syndrome due to the coarseness of features (NS39).
Mentions: SOS1 mutation-positive subjects displayed typical facial features (Fig. 3). Macrocephaly was, however, overrepresented compared to the general NS population (61 vs. 12%) [Sharland et al., 1992]. Among these subjects, cardiac defects were frequently observed (89% of cases), with PS, ASD. and VSD being the most recurrent anomalies, while prevalence of HCM was comparable to that observed in PTPN11 mutation-associated NS, occurring in less than 10% of cases [Sarkozy et al., 2009b]. Of note, PS was found to be frequently associated with ASD (35% of cases). Finally, two subjects were documented to present with mandibular multiple giant cell lesions (MGCLs), which were associated with multiple tumors, including abdominal rhabdomyosarcoma, cerebral glioma, and skin granular cell tumors in one subject.

Bottom Line: Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features.Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized.Genotype-phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth.

View Article: PubMed Central - PubMed

Affiliation: IRCCS Casa Sollievo della Sofferenza, Laboratorio Mendel, San Giovanni Rotondo, Italy.

Show MeSH
Related in: MedlinePlus