ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor

@article{Li2019ARAFRM,
  title={ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor},
  author={Dong Li and Michael E. March and {\'A}lvaro Gutierrez-Uzquiza and Charlly Kao and Christoph Seiler and Erin Pinto and Leticia S Matsuoka and Mark R. Battig and Elizabeth Joyce Bhoj and Tara L Wenger and Lifeng Tian and Nora K. Robinson and Tiancheng Wang and Yichuan Liu and Brant M. Weinstein and Matthew R. Swift and Hyun Min Jung and Courtney N Kaminski and Rosetta Chiavacci and Jonathan A Perkins and Michael A Levine and Patrick M Sleiman and Patricia J Hicks and Janet T Strausbaugh and Jean Bello Belasco and Yoav Dori and Hakon Hakonarson},
  journal={Nature Medicine},
  year={2019},
  volume={25},
  pages={1116-1122}
}
The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations1. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation2. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult… Expand
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References

SHOWING 1-10 OF 52 REFERENCES
Somatic NRAS mutation in patient with generalized lymphatic anomaly
TLDR
This work isolated lymphangiomatosis endothelial cells from GLA tissue and identified a somatic mutation in NRAS, which is characterized by high proliferation and survival rates, but displayed impaired capacities for migration and tube formation. Expand
Mutations in RIT1 cause Noonan syndrome – additional functional evidence and expanding the clinical phenotype
TLDR
Additional functional evidence is provided for a causal relationship between pathogenic mutations in RIT1, increased RAS‐MAPK/MEK‐ERK signaling and the clinical phenotype and the associated phenotypic spectrum is expanded. Expand
Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly
TLDR
The pathogenicity of the identified EPHB4 mutation as a novel cause of CCLA is demonstrated and drugs that inhibit mTOR signaling or RAS-MAPK signaling effectively rescued the misbranching phenotype in a comparable manner, suggesting that ERK inhibitors may have therapeutic benefits in such patients with complex lymphatic anomalies. Expand
Contribution of RIT1 mutations to the pathogenesis of Noonan syndrome: Four new cases and further evidence of heterogeneity
TLDR
The role of RIT1 in the pathogenesis of Noonan syndrome is confirmed, and it seems that the identified mutations might alter protein function and therefore, the activity of ERK and P38 MAPK pathways, thus underlying the specific phenotype observed in NS patients. Expand
Spectrum of mutations and genotype–phenotype analysis in Noonan syndrome patients with RIT1 mutations
TLDR
Results delineate the clinical manifestations of RIT1 mutation-positive NS patients: high frequencies of hypertrophic cardiomyopathy, atrial septal defects, and pulmonary stenosis; and lower frequencies of ptosis and short stature. Expand
Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature
TLDR
This report presents two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively. Expand
A Somatic Activating NRAS Variant Associated with Kaposiform Lymphangiomatosis
TLDR
Kaposiform lymphangiomatosis joins a growing group of vascular malformations and tumors caused by somatic activating variants in the RAS/PI3K/mTOR signaling pathways, and will expand treatment options for these high-risk patients as there is potential for use of targeted RAS pathway inhibitors. Expand
LYMPHODYSPLASIA AND KRAS MUTATION: A CASE REPORT AND LITERATURE REVIEW.
TLDR
The clinical data of one case of CFC syndrome, genetically determined by KRAS mutation, that involved chylothorax, lymphedema, sinus pericranii, craniosynostosis, and seizures is described. Expand
Germline CBL mutation associated with a noonan‐like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23
TLDR
A girl with a Noonan‐like phenotype of bilateral ptosis, lymphedema of the lower limbs and moderate intellectual disability, due to a de novo heterozygous mutation in CBL is described, suggesting a specific association of CBL mutations in germ cell tumor predisposition. Expand
Genetics of lymphatic anomalies.
TLDR
Germline mutations have been identified in at least 20 genes that encode proteins acting around VEGFR-3 signaling but also downstream of other tyrosine kinase receptors that explain more than a quarter of the incidence of primary lymphedema, mostly of inherited forms. Expand
...
1
2
3
4
5
...