Limits...
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.

Show MeSH

Related in: MedlinePlus

SOS1 domain structure and location of residues altered in Noonan syndrome. A: Schematic structure of SOS1 and variants identified in the present study. SOS1 protein domains are indicated (DH, DBL homology domain; PH, pleckstrin homology domain; REM, RAS exchanger motif; CDC25, CDC25 domain). Disease-causing mutations and probably pathogenetic/unclassified variants are shown above and below the cartoon, respectively. Residues affected by class 1 mutations/variants are shown in red, while those affected by class 2 and class 3 changes are shown in yellow and green, respectively. Residues affected by substitutions with unpredictable effect on SOS1 function are shown in black. Novel amino acid substitutions are underlined. B: Location of affected residues in SOS1 represented in its inactive conformation, according to the crystal structure of the protein truncated at the C-terminus (residues 1–1049) (PDB ID: 3KSY) [Guerasko et al., 2010]. Cα ribbon trace of the HF (sky blue), DH (sandy brown), PH (plum), REM (dark green), and CDC25 (blue) domains, and the helical linker connecting the PH and REM domains (gray). Mutated residues are indicated with their side chains as thick lines and colored as reported above. Residue Asp309 (uncharacterized mutation p.Asp309Tyr) is shown in purple. Affected residues are listed in Supp. Table S2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3118925&req=5

fig01: SOS1 domain structure and location of residues altered in Noonan syndrome. A: Schematic structure of SOS1 and variants identified in the present study. SOS1 protein domains are indicated (DH, DBL homology domain; PH, pleckstrin homology domain; REM, RAS exchanger motif; CDC25, CDC25 domain). Disease-causing mutations and probably pathogenetic/unclassified variants are shown above and below the cartoon, respectively. Residues affected by class 1 mutations/variants are shown in red, while those affected by class 2 and class 3 changes are shown in yellow and green, respectively. Residues affected by substitutions with unpredictable effect on SOS1 function are shown in black. Novel amino acid substitutions are underlined. B: Location of affected residues in SOS1 represented in its inactive conformation, according to the crystal structure of the protein truncated at the C-terminus (residues 1–1049) (PDB ID: 3KSY) [Guerasko et al., 2010]. Cα ribbon trace of the HF (sky blue), DH (sandy brown), PH (plum), REM (dark green), and CDC25 (blue) domains, and the helical linker connecting the PH and REM domains (gray). Mutated residues are indicated with their side chains as thick lines and colored as reported above. Residue Asp309 (uncharacterized mutation p.Asp309Tyr) is shown in purple. Affected residues are listed in Supp. Table S2.

Mentions: We and others recently reported that missense mutations in SOS1 (MIM♯ 182530) account for a significant proportion of NS [Roberts et al., 2007; Tartaglia et al., 2007; Zenker et al., 2007a]. SOS1 encodes a guanine nucleotide exchange factor (GEF) responsible for stimulating the conversion of RAS from the inactive, GDP-bound to the active, GTP-bound form [Nimnual and Bar-Sagi, 2002]. SOS1 is a large multidomain protein characterized by an N-terminal regulatory portion including tandem histone-like folds (HF), which are followed by a Dbl-homology (DH) domain and a pleckstrin-homology (PH) domain, and a C-terminal catalytic region including the RAS exchanger motif (REM) and CDC25 domains, followed by a tail providing docking sites for adaptor proteins required for receptor anchoring (Fig. 1). The majority of NS-causing SOS1 mutations were observed to affect residues predicted to be implicated in the maintenance of SOS1 in its autoinhibited conformation, and the first biochemical characterizations of mutants consistently documented enhanced protein function and increased signal flow through RAS [Roberts et al., 2007; Tartaglia et al., 2007]. These surveys also indicated that subjects heterozygous for a mutated SOS1 allele tend to exhibit a distinctive phenotype that is characterized by ectodermal abnormalities generally associated with an absence of cognitive deficits [Tartaglia et al., 2007; Zenker et al., 2007a]. We also observed that height was less frequently below the third centile compared with the overall NS population [Tartaglia et al., 2007]. Although available information supports the view that SOS1 is not mutated in cardiofaciocutaneous syndrome (CFCS; MIM♯ 115150) [Zenker et al., 2007a], a condition clinically related to NS, a few individuals with ectodermal manifestations and distinctive facial dysmorphism that might be suggestive of CFCS have recently been reported has having SOS1 mutations [Narumi et al., 2008; Nystrom et al., 2008]. In these subjects, cognitive deficits were generally absent or minor, but at least one case with mental retardation was reported [Narumi et al., 2008].


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)

SOS1 domain structure and location of residues altered in Noonan syndrome. A: Schematic structure of SOS1 and variants identified in the present study. SOS1 protein domains are indicated (DH, DBL homology domain; PH, pleckstrin homology domain; REM, RAS exchanger motif; CDC25, CDC25 domain). Disease-causing mutations and probably pathogenetic/unclassified variants are shown above and below the cartoon, respectively. Residues affected by class 1 mutations/variants are shown in red, while those affected by class 2 and class 3 changes are shown in yellow and green, respectively. Residues affected by substitutions with unpredictable effect on SOS1 function are shown in black. Novel amino acid substitutions are underlined. B: Location of affected residues in SOS1 represented in its inactive conformation, according to the crystal structure of the protein truncated at the C-terminus (residues 1–1049) (PDB ID: 3KSY) [Guerasko et al., 2010]. Cα ribbon trace of the HF (sky blue), DH (sandy brown), PH (plum), REM (dark green), and CDC25 (blue) domains, and the helical linker connecting the PH and REM domains (gray). Mutated residues are indicated with their side chains as thick lines and colored as reported above. Residue Asp309 (uncharacterized mutation p.Asp309Tyr) is shown in purple. Affected residues are listed in Supp. Table S2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: SOS1 domain structure and location of residues altered in Noonan syndrome. A: Schematic structure of SOS1 and variants identified in the present study. SOS1 protein domains are indicated (DH, DBL homology domain; PH, pleckstrin homology domain; REM, RAS exchanger motif; CDC25, CDC25 domain). Disease-causing mutations and probably pathogenetic/unclassified variants are shown above and below the cartoon, respectively. Residues affected by class 1 mutations/variants are shown in red, while those affected by class 2 and class 3 changes are shown in yellow and green, respectively. Residues affected by substitutions with unpredictable effect on SOS1 function are shown in black. Novel amino acid substitutions are underlined. B: Location of affected residues in SOS1 represented in its inactive conformation, according to the crystal structure of the protein truncated at the C-terminus (residues 1–1049) (PDB ID: 3KSY) [Guerasko et al., 2010]. Cα ribbon trace of the HF (sky blue), DH (sandy brown), PH (plum), REM (dark green), and CDC25 (blue) domains, and the helical linker connecting the PH and REM domains (gray). Mutated residues are indicated with their side chains as thick lines and colored as reported above. Residue Asp309 (uncharacterized mutation p.Asp309Tyr) is shown in purple. Affected residues are listed in Supp. Table S2.
Mentions: We and others recently reported that missense mutations in SOS1 (MIM♯ 182530) account for a significant proportion of NS [Roberts et al., 2007; Tartaglia et al., 2007; Zenker et al., 2007a]. SOS1 encodes a guanine nucleotide exchange factor (GEF) responsible for stimulating the conversion of RAS from the inactive, GDP-bound to the active, GTP-bound form [Nimnual and Bar-Sagi, 2002]. SOS1 is a large multidomain protein characterized by an N-terminal regulatory portion including tandem histone-like folds (HF), which are followed by a Dbl-homology (DH) domain and a pleckstrin-homology (PH) domain, and a C-terminal catalytic region including the RAS exchanger motif (REM) and CDC25 domains, followed by a tail providing docking sites for adaptor proteins required for receptor anchoring (Fig. 1). The majority of NS-causing SOS1 mutations were observed to affect residues predicted to be implicated in the maintenance of SOS1 in its autoinhibited conformation, and the first biochemical characterizations of mutants consistently documented enhanced protein function and increased signal flow through RAS [Roberts et al., 2007; Tartaglia et al., 2007]. These surveys also indicated that subjects heterozygous for a mutated SOS1 allele tend to exhibit a distinctive phenotype that is characterized by ectodermal abnormalities generally associated with an absence of cognitive deficits [Tartaglia et al., 2007; Zenker et al., 2007a]. We also observed that height was less frequently below the third centile compared with the overall NS population [Tartaglia et al., 2007]. Although available information supports the view that SOS1 is not mutated in cardiofaciocutaneous syndrome (CFCS; MIM♯ 115150) [Zenker et al., 2007a], a condition clinically related to NS, a few individuals with ectodermal manifestations and distinctive facial dysmorphism that might be suggestive of CFCS have recently been reported has having SOS1 mutations [Narumi et al., 2008; Nystrom et al., 2008]. In these subjects, cognitive deficits were generally absent or minor, but at least one case with mental retardation was reported [Narumi et al., 2008].

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