Germline gain-of-function mutations in RAF1 cause Noonan syndrome

@article{Razzaque2007GermlineGM,
  title={Germline gain-of-function mutations in RAF1 cause Noonan syndrome},
  author={Mohammad Abdur Razzaque and Tsutomu Nishizawa and Yuta Komoike and Hisato Yagi and Michiko Furutani and R. Merinas Amo and Mitsuhiro Kamisago and Kazuo Momma and Hiroshi Katayama and Masao Nakagawa and Yuko Fujiwara and Masaki Matsushima and Katsumi Mizuno and Mika Tokuyama and Hamao Hirota and Jun Muneuchi and Toru Higashinakagawa and Rumiko Matsuoka},
  journal={Nature Genetics},
  year={2007},
  volume={39},
  pages={1013-1017}
}
Noonan syndrome is characterized by short stature, facial dysmorphia and a wide spectrum of congenital heart defects. Mutations of PTPN11, KRAS and SOS1 in the RAS-MAPK pathway cause ∼60% of cases of Noonan syndrome. However, the gene(s) responsible for the remainder are unknown. We have identified five different mutations in RAF1 in ten individuals with Noonan syndrome; those with any of four mutations causing changes in the CR2 domain of RAF1 had hypertrophic cardiomyopathy (HCM), whereas… 
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TLDR
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TLDR
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TLDR
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Clinical and molecular characterization of 40 patients with Noonan syndrome.
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References

SHOWING 1-10 OF 28 REFERENCES
Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome
TLDR
It is reported that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor, and this finding defines a new mechanism by which upregulation of the RAS pathway can profoundly change human development.
Germline gain-of-function mutations in SOS1 cause Noonan syndrome
TLDR
SOS1 mutants are identified as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation.
Germline KRAS mutations cause Noonan syndrome
TLDR
These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras.
Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype.
TLDR
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 theGuanine 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.
PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.
TLDR
The spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS revealed that pulmonic stenosis was more prevalent among the group of subjects with NS who had PTP N11 mutations than it was in the group without them, andotype-phenotype analysis revealed that hypertrophic cardiomyopathy was less prevalent among those with PTPn11 mutations.
Germline Mutations in Genes Within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome
TLDR
It is demonstrated that heterogeneous de novo missense mutations in three genes within the mitogen-activated protein kinase (MAPK) pathway cause CFC syndrome, and the involvement of the MAPK pathway in human development will provide a molecular diagnosis of CFC Syndrome.
Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction.
TLDR
All of the syndromes discussed in this article now can be understood to constitute a class of disorders caused by dysregulated RAS-MAPK signaling.
Germline Mutations in Components of the Ras Signaling Pathway in Noonan Syndrome and Related Disorders
TLDR
It is found that the mutant K-Ras proteins encoded by NS-associated alleles have less pronounced biochemical defects than known Ras oncoproteins, which likely explains why these mutations are tolerated in the germline.
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome
TLDR
It is shown that missense mutations in PTPN11—a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains—cause Noonan syndrome and account for more than 50% of the cases that were examined.
Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome
TLDR
Dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders of Cardio-facio-cutaneous syndrome, which phenotypically overlaps with Noonan and Costello syndrome.
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