Mutational and functional analysis of the neurofibromatosis type 1 ( NF1 ) gene

Upadhyaya, Meena; Osborn, Michael J.; Maynard, Julie; Kim, Mee Rhan; Tamanoi, Fuyuhiko; Cooper, David Neil

doi:10.1007/s004390050317

Cited by 104 publications

(76 citation statements)

References 22 publications

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“…This may be due to our smaller patient cohort. K1423 appears to be critical for the maintenance of GAP activity (Upadhyaya et al, 1997). This residue is conserved in the GAP domains of human and murine neurofibromin and was initially thought to be involved in protein interaction and catalysis.…”

Section: Discussionmentioning

confidence: 99%

Novel and recurrent mutations in theNF1 gene in Italian patients with neurofibromatosis type 1

et al. 2004

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Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans, affecting 1 in 3500 individuals. NF1 is a fully penetrant exhibiting a mutation rate some 10-fold higher compared to most other disease genes. As a consequence, a high number of cases (up to 50%) are sporadic. Mutation detection is complex due to the large size of NF1 gene, the presence of pseudogenes and the great variety of lesions. In the present study we attempted to delineate the NF1 mutational spectrum in the Italian population reporting four-year experience with the direct analysis of the whole NF1 coding region in 110 unrelated subjects affected by NF1. For each patient, the whole coding sequence and all splice sites were studied for mutations, either by the protein truncation test (PTT), or, most often, by denaturing high performance liquid chromatography (DHPLC). Mutations were identified in 75 (68%) patients. Twenty-two mutations were found to be novel. The detection rate for the different methods was 7/18 (39%) for PTT, and 68/103 (66%) for DHPLC. The mutations were evenly distributed along the NF1 coding sequence. Thirty-two of the 75 unrelated NF1 patients in which germline mutations were identified (32/75, 43%) harbour 23 different recurrent mutations. Fifteen sequence variants likely to represent nonpathogenic polymorphisms were observed at the NF1 locus. Genotype-phenotype analysis was unable to detect any obvious correlation.

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Section: Discussionmentioning

confidence: 99%

Novel and recurrent mutations in theNF1 gene in Italian patients with neurofibromatosis type 1

et al. 2004

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“…NF1 encodes neurofibromin, a RAS-GTPase-activating protein (RAS-GAP). Although most causative NF1 point mutations result in premature translation termination (18), some disease-associated missense mutations encode unstable NF1 proteins without affecting NF1 mRNA levels (19), and others impair RAS-GAP activity (20)(21)(22). The leucine at position 1361 of NF1 is located in the GAP-related domain (NF1-GRD) and is highly conserved (Fig.…”

Section: Significancementioning

confidence: 99%

Next-generation sequencing identifies rare variants associated with Noonan syndrome

Chen

Yin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

166

148

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Noonan syndrome (NS) is a relatively common genetic disorder, characterized by typical facies, short stature, developmental delay, and cardiac abnormalities. Known causative genes account for 70-80% of clinically diagnosed NS patients, but the genetic basis for the remaining 20-30% of cases is unknown. We performed nextgeneration sequencing on germ-line DNA from 27 NS patients lacking a mutation in the known NS genes. We identified gainof-function alleles in Ras-like without CAAX 1 (RIT1) and mitogenactivated protein kinase kinase 1 (MAP2K1) and previously unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2) that are likely to cause NS in these patients. Expression of the mutant RASA2, MAP2K1, or RIT1 alleles in heterologous cells increased RAS-ERK pathway activation, supporting a causative role in NS pathogenesis. Two patients had more than one disease-associated variant. Moreover, the diagnosis of an individual initially thought to have NS was revised to neurofibromatosis type 1 based on an NF1 nonsense mutation detected in this patient. Another patient harbored a missense mutation in NF1 that resulted in decreased protein stability and impaired ability to suppress RAS-ERK activation; however, this patient continues to exhibit a NS-like phenotype. In addition, a nonsense mutation in RPS6KA3 was found in one patient initially diagnosed with NS whose diagnosis was later revised to Coffin-Lowry syndrome. Finally, we identified other potential candidates for new NS genes, as well as potential carrier alleles for unrelated syndromes. Taken together, our data suggest that nextgeneration sequencing can provide a useful adjunct to RASopathy diagnosis and emphasize that the standard clinical categories for RASopathies might not be adequate to describe all patients.human genetics | developmental diseases | whole exome sequencing | PTPN11 | RAS

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“…This downregulation of active Ras is thought to account for the tumor suppressor function of neurofibromin (13). Mutations affecting the Ras-GAP activity of neurofibromin have been identified in NF1 patients and NF1-related malignancies (14)(15)(16), and downstream effectors of Ras signaling are activated in these cells. In particular, the demonstration of clinical NF1 in a family with a point mutation in the GRD leading to the specific loss of Ras-GAP activity without marked disruption of the protein structure suggests the necessity of this domain for tumor suppressor function (15).…”

Section: Introductionmentioning

confidence: 99%

The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1-/- mice

Ismat

Xu²,

Lü³

et al. 2006

Journal of Clinical Investigation

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Neurofibromatosis type I (NF1; also known as von Recklinghausen's disease) is a common autosomaldominant condition primarily affecting neural crest-derived tissues. The disease gene, NF1, encodes neurofibromin, a protein of over 2,800 amino acids that contains a 216-amino acid domain with Ras-GTPaseactivating protein (Ras-GAP) activity. Potential therapies for NF1 currently in development and being tested in clinical trials are designed to modify NF1 Ras-GAP activity or target downstream effectors of Ras signaling. Mice lacking the murine homolog (Nf1) have mid-gestation lethal cardiovascular defects due to a requirement for neurofibromin in embryonic endothelium. We sought to determine whether the GAP activity of neurofibromin is sufficient to rescue complete loss of function or whether other as yet unidentified functions of neurofibromin might also exist. Using cre-inducible ubiquitous and tissuespecific expression, we demonstrate that the isolated GAP-related domain (GRD) rescued cardiovascular development in Nf1 -/-embryos, but overgrowth of neural crest-derived tissues persisted, leading to perinatal lethality. These results suggest that neurofibromin may possess activities outside of the GRD that modulate neural crest homeostasis and that therapeutic approaches solely aimed at targeting Ras activity may not be sufficient to treat tumors of neural crest origin in NF1.

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Mutational and functional analysis of the neurofibromatosis type 1 ( NF1 ) gene

Cited by 104 publications

References 22 publications

Novel and recurrent mutations in theNF1 gene in Italian patients with neurofibromatosis type 1

Novel and recurrent mutations in theNF1 gene in Italian patients with neurofibromatosis type 1

Next-generation sequencing identifies rare variants associated with Noonan syndrome

The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1-/- mice

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