SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome.
BACKGROUND
Heterozygous gain-of-function mutations in various 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.


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.


CONCLUSIONS
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.
Zenker
Martin
M
Horn
Denise
D
Wieczorek
Dagmar
D
Allanson
Judith
J
Pauli
Silke
S
van der Burgt
Ineke
I
Doerr
Helmuth-Guenther
HG
Gaspar
Harald
H
Hofbeck
Michael
M
Gillessen-Kaesbach
Gabriele
G
Koch
Andreas
A
Meinecke
Peter
P
Mundlos
Stefan
S
Nowka
Anja
A
Rauch
Anita
A
Reif
Silke
S
von Schnakenburg
Christian
C
Seidel
Heide
H
Wehner
Lars-Erik
LE
Zweier
Christiane
C
Bauhuber
Susanne
S
Matejas
Verena
V
Kratz
Christian P
CP
Thomas
Christoph
C
Kutsche
Kerstin
K
D000595:Amino Acid Sequence; D001827:Body Height; D003251:Constriction, Pathologic; D005260:Female; D006331:Heart Diseases / Q000151:congenital / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009634:Noonan Syndrome / Q000235:genetics*; D020837:SOS1 Protein / Q000235:genetics* / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D012871:Skin Diseases / Q000235:genetics*; D013577:Syndrome; D020663:ras Guanine Nucleotide Exchange Factors / Q000378:metabolism
D020837:SOS1 Protein; D020663:ras Guanine Nucleotide Exchange Factors