Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy

  title={Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy},
  author={Bhaswati Pandit and Anna Sarkozy and Len A. Pennacchio and Claudio Carta and Kimihiko Oishi and Simone Martinelli and Edgar A Pogna and Wendy S. Schackwitz and Anna Ustaszewska and Andrew P. Landstrom and J. Martijn Bos and Steve Ommen and Giorgia Esposito and Francesca Romana Lepri and Christian Faul and Peter Mundel and Juan Pedro L{\'o}pez Siguero and Romano Tenconi and Angelo Selicorni and Cesare Rossi and Laura Mazzanti and Isabella Torrente and Bruno Marino and Maria Cristina Digilio and Giuseppe Zampino and Michael J. Ackerman and Bruno Dallapiccola and Marco Tartaglia and Bruce D. Gelb},
  journal={Nature Genetics},
Noonan and LEOPARD syndromes are developmental disorders with overlapping features, including cardiac abnormalities, short stature and facial dysmorphia. Increased RAS signaling owing to PTPN11, SOS1 and KRAS mutations causes ∼60% of Noonan syndrome cases, and PTPN11 mutations cause 90% of LEOPARD syndrome cases. Here, we report that 18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals) and two of six individuals with LEOPARD… 
Co‐occurrence of hypertrophic cardiomyopathy and myeloproliferative disorder in a neonate with Noonan syndrome carrying Thr73Ile mutation in PTPN11
A Japanese female infant with NS carrying the PTPN11 T73I mutation with NS/MPD, complete atrio‐ventricular septal defect, and rapidly progressive HCM is reported.
Noonan syndrome associated with both a new Jnk‐activating familial SOS1 and a de novo RAF1 mutations
To the knowledge, this is the first reported case of a patient harboring mutations in two genes, with an involvement of both Ras and Rac1 pathways, indicating that SOS1 may have a role of modifier gene that might contribute the variable expressivity of the disease, evidencing a genotype–phenotype correlation in the family.
Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation
Clinical manifestations in patients with RAF1 mutations as well as those in NS patients withPTPN11, SOS1, or KRAS mutations previously reported are summarized and it is suggested that the dephosphorylation of S259 is the primary pathogenic mechanism in the activation of RAF1 mutants located in the CR2 domain as well of downstream ERK.
Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome.
Noonan Syndrome: Comparing Mutation-Positive with Mutation-Negative Dutch Patients
A genotype-phenotype analysis of 33 patients with a clinical diagnosis of NS without a PTPN11 mutation indicates that the involvement of novel genes is to be expected, and stresses the importance of the syndrome-specific symptoms of the face, heart and short stature in NS.
Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?
A more severe or atypical phenotype was not observed in a patient with Noonan syndrome presenting mutations in two genes of RAS/MAPK pathway, suggesting that these mutations do not exhibit an additive effect.
Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy.
The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature,
Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: Molecular diversity and associated phenotypic spectrum
To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting BRAF, subjects with a diagnosis of NS, LS, and CFCS were screened for the entire coding sequence of the gene.
PTPN11-associated mutations in the heart: has LEOPARD changed Its RASpots?


Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome
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 KRAS mutations cause Noonan syndrome
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 gain-of-function mutations in SOS1 cause Noonan syndrome
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.
PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.
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.
PTPN11 (Shp2) Mutations in LEOPARD Syndrome Have Dominant Negative, Not Activating, Effects*
The results establish that the pathogenesis of LS and NS is distinct and suggest that these disorders should be distinguished by mutational analysis rather than clinical presentation.
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome
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.
Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.
It is demonstrated that ML/LEOPARD syndrome and NS are allelic disorders and the detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the ML/LeOPARD-syndrome subtype of NS.
Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype.
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.
Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome
The cardiac phenotypes in patients with Noonan syndrome and those with multiple lentigines LEOPARD syndrome with PTPN11 mutations are rather dissimilar, with pulmonary valve stenosis prevailing in the former and hypertrophic cardiomyopathy in the latter.
Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.
It is demonstrated that NS-causative mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated ones and that the recurrent LS-causing Y279C and T468M amino acid substitutions engender loss of SHp-2 catalytic activity, identifying a previously unrecognized behavior for this class of missense PTPN11 mutations.