Germline Missense Mutations Affecting KRAS Isoform B Are Associated with a Severe Noonan Syndrome Phenotype

Department of Experimental Medicine, Sapienza University of Rome, Roma, Latium, Italy
The American Journal of Human Genetics (Impact Factor: 10.93). 08/2006; 79(1):129-35. DOI: 10.1086/504394
Source: PubMed


Noonan syndrome (NS) is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart disease, and multiple skeletal and hematologic defects. NS is an autosomal dominant trait and is genetically heterogeneous. Gain of function of SHP-2, a protein tyrosine phosphatase that positively modulates RAS signaling, is observed in nearly 50% of affected individuals. Here, we report the identification of heterozygous KRAS gene mutations in two subjects exhibiting a severe NS phenotype with features overlapping those of cardiofaciocutaneous and Costello syndromes. Both mutations were de novo and affected exon 6, which encodes the C-terminal portion of KRAS isoform B but does not contribute to KRAS isoform A. Structural analysis indicated that both substitutions (Val152Gly and Asp153Val) perturb the conformation of the guanine ring-binding pocket of the protein, predicting an increase in the guanine diphosphate/guanine triphosphate (GTP) dissociation rate that would favor GTP binding to the KRASB isoform and bypass the requirement for a guanine nucleotide exchange factor.

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    • "Described KRAS mutations (p.Lys5Asn, p.Val14Ile, p.Gln22Glu, p.Gln22Arg, p.Pro34Leu, p.Pro34Arg, p.Thr58Ile, p.Gly60Arg, p.Asp134Val, p.Phe156Leu, p.Val152Gly, and p.Asp153Val) are regularly associated with CHD (6-10). Extremely severe phenotype cases of NS and other RASopathies are typically caused only by specific mutations, resulting in overall signal flow dysregulation of the RAS-MAPK pathway (9,11,12). "
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    ABSTRACT: Noonan syndrome is a relatively common and heterogeneous genetic disorder, including congenital heart defect in more than half of the cases. If the defect is not large, life expectancy is normal. Here we report on a case of an infant with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy with lethal outcome, in whom we identified a novel mutation in the KRAS gene. This heterozygous unclassified missense variant in exon 3: c.179G> T (p.Gly60Val) might be associated with a lethal form of Noonan syndrome. The malignant clinical course of the disease and the lethal outcome in an infant only a few months old might be connected to RAS-mitogen-activated protein kinase pathway hyperactivation, consequently promoting cell growth and proliferation, leading to rapidly progressive hypertrophic cardiomyopathy. Further biochemical and functional studies are needed to confirm this hypothesis.
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    • "Germline mutations in the proto-oncogene RAS are found in Costello (HRAS) [Aoki et al., 2005], Noonan (KRAS) [Schubbert et al., 2006] and CFC (KRAS) [Niihori et al., 2006] syndrome. Given the association between germline HRAS and KRAS mutations and RAS- MAPK syndromes, several authors screened the NRAS gene in cohorts of patients with Noonan, Costello or CFC syndrome, but they failed to find any mutation [Aoki et al., 2005; Carta et al., 2006; Roberts et al., 2007]. "
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    ABSTRACT: Noonan syndrome is a genetically heterogeneous disorder caused by mutations in PTPN11, SOS1, RAF1 and less frequently in KRAS, NRAS or SHOC2. Here, we performed mutation analysis of NRAS and SHOC2 in 115 PTPN11, SOS1, RAF1, and KRAS mutation-negative individuals. No SHOC2 mutations were found, but we identified 3 NRAS mutations in 3 probands. One NRAS mutation was novel. The phenotype associated with germline NRAS mutations is variable. Our results confirm that a small proportion of Noonan syndrome patients carry germline NRAS mutations.
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    • "Residues 116–119 of Ras have sequence homology with a variety of GTP-binding proteins and interact with the guanine base. Mutations in this region might hinder its binding with the guanine nucleotide base and result in the increased rate of GDP–GTP exchange [Clanton et al., 1986; Der et al., 1986; Walter et al., 1986; Barbacid, 1990; Carta et al., 2006; Zenker et al., 2007; Denayer et al., 2008] "
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    ABSTRACT: Noonan syndrome (NS) is the most common non-chromosomal syndrome seen in children and is characterized by short stature, dysmorphic facial features, chest deformity, a wide range of congenital heart defects and developmental delay of variable degree. Mutations in the Ras/mitogen-activated protein kinase (MAPK) signaling pathways cause about 70% of NS cases with a KRAS mutation present in about 2%. In a cohort of 65 clinically confirmed NS patients of Japanese origin, we screened for mutations in the RAS genes by direct sequencing. We found a novel mutation in KRAS with an amino acid substitution of asparagine to serine at codon 116 (N116S). We analyzed the biological activity of this mutant by ectopic expression of wild-type or mutant KRAS. NS-associated KRAS mutation resulted in Erk activation and active Ras-GTP levels, and exhibited mild cell proliferation. In addition, kras-targeted morpholino knocked-down zebrafish embryos caused heart and craniofacial malformations, while the expression of mutated kras resulted in maldevelopment of the heart. Our findings implicate that N116S change in KRAS is a hyperactive mutation which is a causative agent of NS through maldevelopment of the heart.
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