Alterations in RAS-MAPK Genes in 200 Spanish Patients With Noonan and Other Neuro-Cardio-Facio-Cutaneous Syndromes. Genotype and Cardiopathy

Ezquieta, Begoña; Santomé, José L.; Carcavilla, Atilano; Guillén‐Navarro, Encarna; Pérez-Aytés, Antonio; Pozo, Jaime Sánchez del; García‐Miñaúr, Sixto; Castillo, Emilia; Alonso, Milagros; Vendrell, Teresa; Santana, Alfredo; Maroto, Enrique E.; Galbis, Liliana

doi:10.1016/j.rec.2011.12.017

Cited by 14 publications

(19 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These variants accounted approximately for 1% (95% CI, 0.6%–1.6%) of cases, specifying a novel mutation cluster causing NS (Table ). All mutations were novel, the only exception being the c.781C > T transition (p.L261F) that had previously been reported in one NS patient [Ezquieta et al., ]. This lesion, as well as the c.785T > G (p.L262R) and c.794G > A (p.R265Q) changes were shown to occur as de novo events by genotyping of parental DNAs in seven cases, while they co‐segregated with the disease in four families.…”

Section: Resultsmentioning

confidence: 66%

Structural, Functional, and Clinical Characterization of a NovelPTPN11Mutation Cluster Underlying Noonan Syndrome

et al. 2017

View full text Add to dashboard Cite

Germline mutations in PTPN11, the gene encoding the Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu , Leu , and Arg in 16 unrelated individuals with clinical diagnosis of NS or with features suggestive for this disorder, specifying a novel disease-causing mutation cluster. Expression of the mutant proteins in HEK293T cells documented their activating role on MAPK signaling. Structural data predicted a gain-of-function role of substitutions at residues Leu and Arg exerted by disruption of the N-SH2/PTP autoinhibitory interaction. Molecular dynamics simulations suggested a more complex behavior for changes affecting Leu , with possible impact on SHP2's catalytic activity/selectivity and proper interaction of the PTP domain with the regulatory SH2 domains. Consistent with that, biochemical data indicated that substitutions at codons 262 and 265 increased the catalytic activity of the phosphatase, while those affecting codon 261 were only moderately activating but impacted substrate specificity. Remarkably, these mutations underlie a relatively mild form of NS characterized by low prevalence of cardiac defects, short stature, and cognitive and behavioral issues, as well as less evident typical facial features.

show abstract

Section: Resultsmentioning

confidence: 66%

Structural, Functional, and Clinical Characterization of a NovelPTPN11Mutation Cluster Underlying Noonan Syndrome

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Clinical features such as pulmonary stenosis (PS), short stature and thoracic deformities are more consistently associated with PTPN11 mutations than other clinical features [10][11][12][13][14]. The association of congenital heart defects in some studies is greater than 80% [1,10,11,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] indicating that NS is the second syndrome after Down syndrome with respect to frequency of cardiac defects.…”

Section: Introductionmentioning

confidence: 99%

Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations

et al. 2020

View full text Add to dashboard Cite

Background: Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. In several studies PTPN11 is one of the genes with a significant number of pathogenic variants in NS-affected patients. Therefore, clinically diagnosed NS individuals are initially tested for pathogenic variants in PTPN11 gene to confirm the relationship before studying genotype-phenotype correlation. Methods: Individuals (363) with clinically diagnosed NS from four hospitals in South India were recruited and the exons of PTPN11 gene were sequenced. Results: Thirty-two previously described pathogenic variants in eight different exons in PTPN11 gene were detected in 107 patients, of whom 10 were familial cases. Exons 3, 8 and 13 had the highest number of pathogenic variants. The most commonly identified pathogenic variants in this series were in exon 8 (c.922A > G, c.923A > G), observed in 22 of the affected. Congenital cardiac anomalies were present in 84% of the mutation-positive cohort, the majority being defects in the right side of the heart. The most common facial features were downward-slanting palpebral fissures, hypertelorism and low-set posteriorly rotated ears. Other clinical features included short stature (40%), pectus excavatum (54%) and, in males, unilateral or bilateral cryptorchidism (44%). Conclusion: The clinical features and mutational spectrum observed in our cohort are similar to those reported in other large studies done worldwide. This is the largest case series of NS-affected individuals with PTPN11 mutations described till date from India.

show abstract

“…The second group of mutations (8.1%) affects the adjacent residues Ser612 and Leu613 located C‐terminally to the CR3 domain, and the third group (7.9%) affects the two amino acid residues Asp486 and Thr491 within the activation segment of the kinase domain (Croonen et al, ; Hartill, Dillon, Warren, & Blyth, ; Hopper, Feinstein, Manning, Benitz, & Hudgins, ; Ko, Kim, Kim, & Yoo, ; Kobayashi et al, ; Pandit et al, ; Ratola et al, ; Razzaque et al, ; Sana et al, ; Schulz, Frober, Kraus, & Schneider, ). Only two amino acid substitutions in CR3 have been described so far (4%): p.(Ser427Gly) was found in mother and son with NS as well as in an unrelated patient (Kobayashi et al, ; Zebisch et al, ), and p.(Glu478Lys) was found in one patient (Ezquieta et al, ). Greater RAF1 kinase activity was determined for amino acid substitutions located in CR2, CR3, and at the end of CR3, while mutations affecting residues 486 and 491 impaired kinase activity (Kobayashi et al, ; Pandit et al, ; Razzaque et al, ).…”

Section: Introductionmentioning

confidence: 99%

The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor

Harms

Alawi

Amor

et al. 2017

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Noonan syndrome is characterized by typical craniofacial dysmorphism, postnatal growth retardation, congenital heart defect, and learning difficulties and belongs to the RASopathies, a group of neurodevelopmental disorders caused by germline mutations in genes encoding components of the RAS-MAPK pathway. Mutations in the RAF1 gene are associated with Noonan syndrome, with a high prevalence of hypertrophic cardiomyopathy (HCM). RAF1 mutations cluster in exons encoding the conserved region 2 (CR2), the kinase activation segment of the CR3 domain, and the C-terminus. We present two boys with Noonan syndrome and the identical de novo RAF1 missense variant c.1082G>C/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a RAF1 allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial-like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well-established association of NS with malignant tumors, especially childhood hemato-oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots.

show abstract

Alterations in RAS-MAPK Genes in 200 Spanish Patients With Noonan and Other Neuro-Cardio-Facio-Cutaneous Syndromes. Genotype and Cardiopathy

Cited by 14 publications

References 32 publications

Structural, Functional, and Clinical Characterization of a NovelPTPN11Mutation Cluster Underlying Noonan Syndrome

Structural, Functional, and Clinical Characterization of a NovelPTPN11Mutation Cluster Underlying Noonan Syndrome

Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations

The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor

Contact Info

Product

Resources

About