LETTER TO JMG
SOS1 is the second most common Noonan gene but plays no
major role in cardio-facio-cutaneous syndrome
Martin Zenker, Denise Horn, Dagmar Wieczorek, Judith Allanson, Silke Pauli, Ineke van der Burgt,
Helmuth-Guenther Doerr, Harald Gaspar, Michael Hofbeck, Gabriele Gillessen-Kaesbach, Andreas
Koch, Peter Meinecke, Stefan Mundlos, Anja Nowka, Anita Rauch, Silke Reif, Christian von
Schnakenburg, Heide Seidel, Lars-Erik Wehner, Christiane Zweier, Susanne Bauhuber, Verena
Matejas, Christian P Kratz, Christoph Thomas, Kerstin Kutsche
............................................................... ............................................................... .....
J Med Genet 2007;44:651–656. doi: 10.1136/jmg.2007.051276
Background: Heterozygous gain-of-function mutations in var-
ious genes encoding proteins of the Ras-MAPK signalling
cascade have been identified as the genetic basis of Noonan
syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS).
Mutations of SOS1, the gene encoding a guanine nucleotide
exchange factor for Ras, have been the most recent discoveries
in patients with NS, but this gene has not been studied in
patients with CFCS.
Methods and results: We investigated SOS1 in a large cohort
of patients with disorders of the NS–CFCS spectrum, who had
previously tested negative for mutations in PTPN11, KRAS,
BRAF, MEK1 and MEK2. Missense mutations of SOS1 were
discovered in 28% of patients with NS. In contrast, none of the
patients classified as having CFCS was found to carry a
pathogenic sequence change in this gene.
Conclusion: We have confirmed SOS1 as the second major
gene for NS. Patients carrying mutations in this gene have a
distinctive phenotype with frequent ectodermal anomalies such
as keratosis pilaris and curly hair. However, the clinical picture
associated with SOS1 mutations is different from that of CFCS.
These findings corroborate that, despite being caused by gain-
of-function mutations in molecules belonging to the same
pathway, NS and CFCS scarcely overlap genotypically.
cascade is most likely the common pathogenetic mechanism
underlying Noonan syndrome (NS; OMIM 163950) and two
related disorders, cardio-facio-cutaneous syndrome (CFCS;
OMIM 115150) and Costello syndrome (OMIM 218040).1–5
These disorders share a common pattern of congenital
anomalies, including typical heart defects, craniofacial dys-
morphism, short stature, skeletal anomalies and varying
degrees of mental retardation.6–8PTPN11, encoding the protein
tyrosine phosphatase SHP-2, which transduces signals from
activated growth factor receptors to Ras and other signalling
molecules, was first discovered as the major gene mutated in
NS.1In contrast, CFCS was found to be associated with
mutations in any of the genes BRAF, MEK1 or MEK2, encoding
components of the well-known B-Raf-MEK-ERK signalling
cascade downstream from Ras.3 4Mutations in the KRAS gene
have been found in patients with NS and CFCS,
specific mutations in HRAS have been detected in the vast
majority of people with Costello syndrome.2Nevertheless, no
genetic defect has been found in ,30% of paients with CFCS
and in ,50% of those with NS until recently.
esearch data accumulated during the past few years have
significantly contributed to our current understanding
that constitutive activation of the Ras-MAPK signalling
3 5 9 10and
To identify novel genes for these disorders, we screened
additional functional candidates encoding proteins involved in
the Ras-MAPK signalling pathway, including SOS1. While this
work was in progress, two other groups reported gain-of-
function mutations of SOS1 in 17–20% of PTPN11 mutation-
negative patients with NS.11 12
exchange factor (GEF) for Ras catalysing the conversion of
the inactive GDP-bound form of Ras to its active GTP-bound
form. The precise mechanisms of SOS1 activation are incom-
pletely understood. Conformational changes within SOS1
allowing Ras to access its allosteric binding site that, in the
inactive state, is blocked by an intramolecular interaction
involving the Dbl homology–pleckstrin homology (DH-PH) unit
are presumed to play an important role.13–15NS-associated SOS1
mutations have been suggested to result in a release of
autoinhibition, followed by an increase in GEF activity
subsequently leading to enhanced levels of active, GTP-bound
Ras.11 12Indeed, by analysing representative mutant SOS1
proteins, these NS-associated mutations were found to cause
a gain-of-function effect, as shown by increased Ras and ERK
activation in vitro.11 12
SOS1 encodes a guanine
PATIENTS AND METHODS
Ethics approval for this study was obtained from the Ethics
Committee of the University of Erlangen-Nuremberg, and
informed consent for the genetic analyses was received from
patients or their legal guardians.
Our initial study population (group 1) consisted of 85
clinically well-characterised patients with NS and CFCS, who
were assessed by experienced clinical geneticists. In total, 53
patients (group 1A) were classified as having NS according to
established diagnostic criteria,16 17and 21 patients (group 1B)
were given the diagnosis of CFCS, supported by the published
CFC index.18In 11 patients (group 1C), a clear-cut assignment
to one of these two syndromes was not possible. This subgroup
comprised six patients with normal mental development
suggestive of NS but ectodermal anomalies similar to those
seen in CFCS, and five infants classified as ‘‘borderline’’, as they
had a phenotype that could evolve into either NS or CFCS. All
study participants had previously tested negative for mutations
in the genes PTPN11, KRAS and HRAS. Patients in groups 1B and
1C had been screened for mutations in BRAF, MEK1 and MEK2
with normal results.
In addition, we included a second cohort (group 2),
comprising 80 patients referred for molecular diagnosis of NS
Abbreviations: CFCS, cardio-facio-cutaneous syndrome; DH-PH, Dbl
homology–pleckstrin homology; GEF, guanine exchange factor; NS,
Noonan syndrome; OMIM, Online Mendelian Inheritance in Man
and tested negative for a PTPN11 mutation. This group
contained a considerable number of cases with a mild or
atypical phenotype. A PTPN11 mutation detection rate of 18% in
the original cohort, from which group 2 was derived, reflects
the clinical and genetic heterogeneity in this group.
DNA specimens obtained from blood cells were screened for
SOS1 mutations by direct sequencing of all coding exons (ABI
BigDye Terminator Sequencing Kit V.2.1; Applied Biosystems,
Weiterstadt, Germany) using an automated capillary sequencer
(ABI 3730, Applied Biosystems). Primer pairs and PCR
conditions are available on request. In group 2, we restricted
analysis to those exons in which mutations have been found in
this and previous studies (exons 3, 6–8, 10–14, 16 and 19).11 12
Where mutations were shown to have arisen de novo, we
verified declared relationships by genotyping at 10 microsatel-
lite loci for each patient and both parents. PCR products from
one patient showing two sequence alterations in exon 10 were
cloned in Escherichia coli (TOPO TA Cloning Kit; Invitrogen,
Karlsruhe, Germany and One Shot, Invitrogen) to determine
whether these alterations occurred on the same allele.
Structural analysis of novel SOS1 variations
The potential effects of novel SOS1 variations detected in this
study were analysed in more detail using the known three-
dimensional structures of SOS114 15 19 20
program PyMOL (http://www.pymol.org). Figures were prepared
using PyMOL and Adobe Photoshop (Adobe Systems Inc., USA).
and the computer
SOS1 variations and associated phenotypes
Overall, we found 18 different heterozygous SOS1 sequence
variations predicting amino acid changes of the encoded SOS1
protein in 28 unrelated patients, including 25 sporadic cases
and 3 patients with a positive family history for NS (table 1).
Three of the observed sequence alterations represent possible
polymorphisms: the variation c.1964CRT (P655L) which has
previously been identified as a polymorphism12was found in 4
of the 28 patients. In line with the assumption that this is a
non-pathogenic change, we also identified it in unaffected
parents. One female patient with features of NS and significant
ectodermal features (group 1C) was found to carry a novel
sequence alteration, c.2999GRA (S1000N), inherited from her
father, who lacked any clinical signs of NS. Based on this
observation and the fact that S1000 is not highly conserved
through evolution (fig 1), we regarded this variant as a
probable neutral polymorphism. Another novel missense
change, c.233TRG, affecting the evolutionarily conserved
residue F78 (fig 1) was discovered in a male patient with
many features of NS and in his mother. She was said to be
clinically normal but could not be examined personally for the
presence of possible minor signs of NS. Because we cannot be
sure if F78C is a pathogenic mutation or polymorphism, we
conservatively counted this patient among the SOS1 mutation-
The remaining 15 SOS1 sequence alterations observed in 22
unrelated patients were regarded as pathogenic mutations; 10
nucleotide variations identified in our cohort have been
established as causative mutations previously,11 12whereas five
are novel (table 1). Of the novel ones, mutation c.1300GRA has
the same impact on the protein level as a previously published
mutation (c.1300GRC; G434R).11The remaining four sequence
variations predict novel amino acid changes. One of these,
c.806TRC (M269T), affects the same amino acid residue as the
previously reported mutation M269R.11 12It is likely that both
exchanges of the neutral methionine by a polar residue have
similar consequences on SOS1 protein function. The novel
variations c.1433CRG (P478R) and c.1867TRA (F623I),
detected in two sporadic cases, were regarded as causative
mutations based on de novo occurrence, conservation (fig. 1)
and function (see below). One affected person had two
sequence changes, 1431GRT (Q477H) and 1433CRT (P478L).
Cloning of the amplified product and sequencing of both
parents demonstrated that both changes had occurred de novo
on the same allele (not shown). De novo occurrence of the
respective mutations was also confirmed in all other sporadic
patients except two, for whom parental samples were unavail-
able. These two patients carried the known SOS1 mutations
c.1654ARG (R552G) and c.2536GRA (E846K). In the three
patients with a positive family history of NS, previously
reported SOS1 mutations were found (table 1), which were in
each case inherited from an affected mother. The nucleotide
changes predicting F78C, Q477H, P478L/R, F623I and S1000N
were not found in .150 population-matched controls.
Considering only those cases with bona fide mutations, 18 of
85 patients of group 1 were found to have a SOS1 mutation. A
causative SOS1 alteration was identified in 14 of 53 (26%)
patients in group 1A, 4 of 11 (36%) patients in group 1C, but in
none of the 21 patients with CFCS (group 1B). Only four (5%)
people with SOS1 mutations were identified in group 2.
Clinically, most patients with SOS1 mutations exhibited a
clear NS phenotype (fig 2). One patient from group 2, a girl
carrying the de novo P478R mutation, only had very mild facial
features of NS and short stature, and would not have met the
published strict clinical criteria.17Four patients with SOS1
mutations had been assigned to group 1C; three of them
exhibited significant ectodermal symptoms resembling those
found in CFCS, but had normal psychomotor and mental
development in keeping with the diagnosis of NS, and the
fourth was a young infant defying a clear-cut diagnosis. Facial
features of representative SOS1 mutation-positive cases are
illustrated in figure 2.
For a more detailed phenotypic analysis, we included the 22
index patients with bona fide mutations and the three affected
mothers with a confirmed SOS1 mutation. Comparison of
clinical features in people carrying a SOS1 mutation with those
of our cohort and three other cohorts of PTPN11 mutation-
positive patients21–23revealed a similar spectrum of congenital
heart defects, but a lower frequency of mental retardation or
need for special education, easy bruising, and in males,
cryptorchidism (table 2). These differences become even more
obvious when combining findings of this study with data
published recently.11 12However, a significantly lower preva-
lence of short stature in patients with a SOS1 mutation, as
indicated by previous studies,11 12could not be confirmed in our
cohort. Remarkably, patients with SOS1 mutations commonly
had ectodermal manifestations, including keratosis pilaris of
the face, sparse eyebrows, curly hair, and in one patient,
ichthyosiform skin changes (fig 2). The incidence of ectodermal
manifestations in patients with NS with PTPN11 mutations has
not yet been well documented. By reviewing a cohort (n=42)
of clinically well documented PTPN11 mutation-positive people
mainly derived from our previous study,17we could confirm a
significantly higher prevalence of keratosis pilaris/hyperkerato-
tic skin and curly hair in patients with SOS1 mutations
compared with those with PTPN11 alterations (58% vs 6%
and 78% vs 34%, respectively). Moreover, ocular ptosis was
observed more frequently in patients with NS with SOS1 muta-
tions than in patients with a PTPN11 alteration (80% vs 54%).
Structural assessment of novel SOS1 variants
We analysed in more detail the potential effects of the novel
predicted SOS1 variants F78C and F623I, as well as those of
652Zenker, Horn, Wieczorek, et al
substitutions at residues Q477 and P478, using the known
three-dimensional structures of SOS1.14 15 19 20The invariant
residue F78 is located in the N-terminal histone folds domain.
This residue is predicted to interact indirectly with R552, the
most commonly mutated residue, and substitutions of F78 may
therefore have similar effects to those of mutations at R552.
Q477 and P478 are not located in one of the known mutation
clusters. We were unable to predict the precise consequences of
substitutions of these residues based on structural modelling.
Most likely, they do not directly affect the autoinhibited
(orange), Ras exchanger motif (Rem), Cdc25 and polyproline domains are shown along with previously described Noonan syndrome-associated mutations
(black, top of the figure) and the novel missense changes identified in this study (red, bottom). Asterisks mark those variants also detected in one of the
healthy parents. (B) Partial amino acid sequence alignments of human SOS1 with its orthologues of different species and human SOS2. Amino acids
surrounding the four novel altered amino acids (indicated in red) are shown.
(A) Domain organisation of the human SOS1 protein. Histone-like folds, Dbl homology (DH), pleckstrin homology (PH), helical PH-Rem linker
Missense variants of SOS1
Number of affected
1 sporadic case?
c.[1431GRT; 1433CRT]1 [Q477H; P478L]
1 sporadic case
1 sporadic case
1 sporadic case
1 sporadic case
1 sporadic case
1 sporadic case
1 sporadic case
1 sporadic case
1 sporadic case
2 sporadic cases,
1 familial observation?
1 sporadic case,
1 familial observation?
1 sporadic case,
1 familial observation?
1 sporadic case
4 sporadic cases
1 sporadic case
4 sporadic cases
1 sporadic case**
10 c.1655GRA R552K PH-Rem linker Pathogenic
10c.1656GRT R552S PH-Rem linkerPathogenic
HF, histone-like folds; DH, Dbl homology domain; PH, pleckstrin homology domain; Rem, Ras exchanger motif.
Novel variants are printed in bold type.
*Exon 1 refers to the exon containing the ATG starting codon; ?unaffected mother carries the same variant; `novel
nucleotide exchange predicting a known missense mutation on protein level; 1both sequence changes occurred de novo
on the same allele; ?affected mother–child duo; **unaffected father carries the same variant.
SOS1 plays no major role in cardio-facio-cutaneous syndrome 653
conformation. The highly conserved F623 residue is considered
to play an important role in stabilising the Rem domain by
forming an aromatic interaction with F958. Interestingly,
substitution of F623 by glutamate in a SOS1 mutant protein
composed of the Rem-Cdc25 module has been shown to
decrease exchange activity.24Substitution of F623 by isoleucine
presumably also abolishes aromatic interaction between F958
and F623 and may therefore lead to a reduced guanine
nucleotide exchange activity of SOS1 (see supplementary
information for further details; available online at http://
By screening genes encoding proteins involved in the Ras-
MAPK signalling pathway we have independently discovered
SOS1 mutations in patients with classic features of NS (group
1A) and people with NS with more florid ectodermal symptoms
and signs (group 1C). Taking these two subgroups of our core
study population (group 1) together, our mutation detection
rate reaches 28% among clinically well-characterised patients
who lacked mutations in the previously reported NS and CFCS
genes. This proportion exceeds those in previously published
cohorts (Tartaglia et al 17%; Roberts et al 21%).11 12In aggregate,
the two published studies and our study establish SOS1 as the
second major gene for NS. A SOS1 mutation detection rate of 5%
in group 2 corresponds to the low PTPN11 mutation rate of 18%
in this heterogeneous cohort. It is evident that established
clinical criteria for NS are valid for patients with SOS1
mutations, as only one patient with an SOS1 mutation did not
meet strict diagnostic criteria. Thus, our findings do not support
SOS1 as an important gene for people presenting with a mild or
even atypical NS phenotype.
indicated below and the clinical assignment above each photograph. The female patient classified as having ‘‘mild NS’’ presented only with short stature
and mild facial anomalies. Ichthyosiform skin changes in a patient carrying the mutation E846K are illustrated in the lower right image. Parental/guardian
informed consent was obtained for publication of this figure.
Facial appearance of 13 representative patients with Noonan syndrome (NS) carrying SOS1 mutations. The respective missense mutation is
Clinical manifestations in patients with Noonan syndrome with SOS1 and PTPN11
Total Combined data?
Atrial septal defect
Mental retardation/need for special
Short stature (,3rd centile)
ND, no data.
*p,0.05 (Fisher’s exact test); ?combined data from four large studies: Tartaglia et al,
and Jongmans et al
21Musante et al,
22Zenker et al,
23; `data available only from two of four studies.
654 Zenker, Horn, Wieczorek, et al
People with SOS1 mutations typically display a distinctive
form of NS characterised by frequent ptosis, ectodermal
symptoms and generally normal intelligence, an observation
that has also been made by Tartaglia et al.12However, the
clinical spectrum is broad (as shown in fig 2) making it difficult
to predict the genetic defect of a person with NS based on
clinical appearance, thus we will not change our diagnostic
strategy of first analysing PTPN11 in any patient with NS. In
contrast to previous reports, we did not find a significantly
lower prevalence of short stature in subjects with SOS1
mutations compared with those with PTPN11 mutations.
Differences in patient selection may account for this apparent
discrepancy, as several of our patients were recruited from a
paediatric endocrinology department where they were seen for
One important finding of this study is the absence of SOS1
mutations in patients with the diagnosis of CFCS, who had
tested negative for mutations in the established CFCS genes.
Although the ectodermal manifestations in patients with SOS1
mutations are common and may be similar to those typically
found in CFCS,12the SOS1 phenotype in our study cohort is
distinct from CFCS. The most important discriminating feature
is the absence of significant mental retardation in patients with
SOS1 mutations. Nonetheless, patients with SOS1 mutations
may meet published criteria for CFCS.18This brings into
question the usefulness of the ‘‘CFC index’’ and emphasises
the significance of intellectual functioning level in discriminat-
ing between NS and CFCS. In young children, however, clinical
discrimination between these two conditions, particularly NS
caused by SOS1 mutations, is difficult and may even be
impossible. In such cases, determination of the molecular
defect may have important prognostic implications.
SOS1 mutations associated with NS have been shown to
result in a gain of function,11 12consistent with the concept that
NS and related disorders are caused by hyperactive Ras and
aberrantactivation of the
However, to date, few SOS1 mutant proteins have been
assessed functionally. This study provides the first hint that
NS-associated SOS1 mutations may not uniformly lead to
increased GEF activity, but instead may cause a decrease in
exchange activity of SOS1, as already suggested by Shannon
and Bollag.26The precise consequences of the F623I mutation
remain to be determined by experimental means.
Taken together, our findings reinforce the concept that NS
and CFCS scarcely overlap genotypically.27The pathogenetic
basis of this obvious genotype phenotype correlation remains to
be elucidated. It has been speculated that the influence of Ras
effector pathways other than B-Raf-MEK-ERK or negative
feedback mechanisms differentially affecting proximal and
distal components may account for the phenotypic differences
in patients with NS and CFCS.11 25These emerging correlations
between phenotypes and genotypes in this group of similar
disorders is useful in defining new candidate genes for patients
with NS or CFCS whose underlying genetic defect has yet to be
We are grateful to the patients and families who participated in this
study. We thank Angelika Diem and Inka Jantke for help with
mutation screening. This work was supported by a grant from the
German Research Foundation (DFG) to MZ.
Supplementary material is available online at http://
Martin Zenker, Anita Rauch, Christiane Zweier, Susanne Bauhuber,
Verena Matejas, Institute of Human Genetics, University Hospital Erlangen,
Friedrich-Alexander University Erlangen-Nuremberg, Germany
Denise Horn, Stefan Mundlos, Institute of Medical Genetics, Charite ´,
University Medicine of Berlin, Berlin, Germany
Dagmar Wieczorek, Institut fu ¨r Humangenetik, Universita ¨t Duisburg-Essen,
Judith Allanson, Children’s Hospital of Eastern Ontario, Ottawa, Ontario,
Silke Pauli, Lars-Erik Wehner, Institute of Human Genetics, University of
Goettingen, Goettingen, Germany
Ineke van der Burgt, Department of Human Genetics, University Medical
Center St Radboud, Nijmegen, The Netherlands
Helmuth-Guenther Doerr, Department of Pediatric Endocrinology,
University Children’s Hospital, Erlangen, Germany
Harald Gaspar, Institute of Medical Genetics, University of Zurich, Zurich,
Michael Hofbeck, University Children’s Hospital, Pediatric Cardiology,
Gabriele Gillessen-Kaesbach, Institut fu ¨r Humangenetik, Universita ¨t zu
Lu ¨beck, Lu ¨beck, Germany
Andreas Koch, Department of Pediatric Cardiology, University Children’s
Hospital, Erlangen, Germany
Peter Meinecke, Medizinische Genetik, Altonaer Kinderkrankenhaus,
Anja Nowka, Kerstin Kutsche, Institut fu ¨r Humangenetik,
Universita ¨tsklinikum Hamburg-Eppendorf, Hamburg, Germany
Silke Reif, Institut fu ¨r Humangenetik und Medizinische Biologie, Universita ¨t
Christian von Schnakenburg, Christian P Kratz, Department of Pediatrics
and Adolescent Medicine, University of Freiburg, Freiburg, Germany
Heide Seidel, Institute of Human Genetics, Ludwig-Maximilian University,
Electronic database information
N Online Mendelian Inheritance in Man (OMIM) (for NS,
CFCS and CS). http://www.ncbi.nlm.nih.gov/Omim/
N Gene, for SOS1 genomic (accession number
NC_000002.10) and cDNA (accession number
NM_005633.2) sequences. http://www.ncbi.nlm.nih.-
N Protein Data Bank, for coordinates of DH-PH-Rem-Cdc25
construct of hSOS1 (molecule B of code 1XD4), ternary
Ras-SOS1-RasNGppNHp complex (1NVW) and Ras-
SOS1 (1BKD). http://www.rcsb.org/pdb/home/
N We identified mutations of SOS1 in 28% of patients with
NS who had previously tested negative for mutations in
PTPN11 and KRAS, but not in patients with cardio-facio-
N Five novel mutations were detected, defining additional
mutation hotspots and indicating possible new mechan-
isms of perturbed SOS1 protein function.
N People with SOS1 mutations commonly show ocular
ptosis, curly hair and hyperkeratotic skin, but they seem
to have a lower frequency of mental retardation than
patients with Noonan syndrome and mutations of
SOS1 plays no major role in cardio-facio-cutaneous syndrome 655
Christoph Thomas, Max Planck Institute of Molecular Physiology, Download full-text
Department of Structural Biology, Dortmund, Germany
Competing interests: None declared.
Parental/guardian informed consent was obtained for publication of figure 2.
Correspondence to: Martin Zenker, MD, Institute of Human Genetics,
University of Erlangen-Nuremberg, Schwabachanlage 10, 91054
Erlangen, Germany; firstname.lastname@example.org
Received 2 May 2007
Revised 5 June 2007
Accepted 5 June 2007
Published Online First 23 June 2007
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