SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype

Motta, Marialetizia; Fasano, Giulia; Gredy, Sina; Brinkmann, Julia; Bonnard, Adeline; Şimşek‐Kiper, Pelin Özlem; Güleç, Elif Yılmaz; Essaddam, L.; Ütine, Gülen Eda; Prandi, Ingrid Guarnetti; Venditti, Martina; Pantaleoni, Francesca; Radio, Francesca Clementina; Ciolfi, Andrea; Petrini, Stefania; Consoli, Federica; Vignal, Cédric; Hepbasli, Denis; Ullrich, Melanie; Boer, Elke de; Vissers, Lisenka E.L.M.; Gritli, Sami; Rossi, Cesare; Luca, Alessandro De; Bêcher, S. Ben; Gelb, Bruce D.; Dallapiccola, Bruno; Lauri, Antonella; Chillemi, Giovanni; Schuh, Kai; Cavé, Hélène; Zenker, Martin; Tartaglia, Marco

doi:10.1016/j.ajhg.2021.09.007

Cited by 38 publications

(63 citation statements)

References 80 publications

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“…Knockout of the related Spred2 results in an obsessive-compulsive behavioral phenotype ( Ullrich et al, 2018 ), as well as impaired growth, cardiac hypertrophy, splenomegaly and craniofacial malformation ( Ullrich et al, 2019 ). Interestingly, a recent report described a case series of patients with an autosomal-recessive NS-like phenotype resulting from loss of SPRED2 function ( Motta et al, 2021 ), further validating SPRED2 as a RASopathy gene.…”

Section: Lsmentioning

confidence: 91%

The RASopathies: from pathogenetics to therapeutics

Hebron

Hernandez

Yohe

2022

Disease Models &Amp; Mechanisms

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The RASopathies are a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK pathway. These disorders, including neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome and Legius syndrome, among others, have overlapping clinical features due to RAS/MAPK dysfunction. Although several of the RASopathies are very rare, collectively, these disorders are relatively common. In this Review, we discuss the pathogenesis of the RASopathy-associated genetic variants and the knowledge gained about RAS/MAPK signaling that resulted from studying RASopathies. We also describe the cell and animal models of the RASopathies and explore emerging RASopathy genes. Preclinical and clinical experiences with targeted agents as therapeutics for RASopathies are also discussed. Finally, we review how the recently developed drugs targeting RAS/MAPK-driven malignancies, such as inhibitors of RAS activation, direct RAS inhibitors and RAS/MAPK pathway inhibitors, might be leveraged for patients with RASopathies.

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Section: Lsmentioning

confidence: 91%

The RASopathies: from pathogenetics to therapeutics

Hebron

Hernandez

Yohe

2022

Disease Models &Amp; Mechanisms

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“…The collection of data on the molecular spectrum of mutations for each of these genes has contributed to the appreciation of the differential impact of RASopathy-causing and cancer-associated mutations on protein function and intracellular signaling. He also presented published and unpublished findings on the identification of MAPK1 mutations as a new event underlying a novel RASopathy and on the identification of a second form of recessive NS resulting from biallelic LOF variants in SPRED2 (Motta et al, 2020(Motta et al, , 2021.…”

Section: Advocate Keynote: Finding a Diagnosis And Our Voice As Advoc...mentioning

confidence: 99%

The seventh international RASopathies symposium: Pathways to a cure—expanding knowledge, enhancing research, and therapeutic discovery

Kontaridis

Roberts

Schill³

et al. 2022

American J of Med Genetics Pt A

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RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen‐activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.

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“…2,3 Many of these new insights have arisen from clinical observations of how germline mutations in regulators or components of the Ras/MAPK pathway exhibit a distinct but overlapping phenotype, owing to their common underlying mechanism. 2 This class of congenital developmental disorders came to be referred to as (SPRED2, MIM619745) 4 . Afflicted individuals often present with craniofacial dysmorphisms, ocular, musculoskeletal and cutaneous abnormalities, hypotonia, neurocognitive impairment, cardiac malformations and increased cancer risks.…”

Section: Introductionmentioning

confidence: 99%

“…This class of congenital developmental disorders came to be referred to as “RASopathies”. It encompasses syndromes like Noonan syndrome (caused by mutations in RAF1 (MIM611553), PTPN11 (MIM151110), SOS1 (MIM610733), KRAS (MIM609942) or SHOC2 (MIM607721)), Costello Syndrome ( HRAS , MIM218040), cardiofaciocutaneous syndrome ( BRAF, MAP2K1/2, KRAS ), neurofibromatosis type I ( NF1 , MIM162200), capillary malformation-arteriovenous malformation ( RASA1 , MIM139150), Noonan syndrome 13 (MAPK1, MIM176948) and Noonan syndrome 14 (SPRED2, MIM619745) 4 . Afflicted individuals often present with craniofacial dysmorphisms, ocular, musculoskeletal and cutaneous abnormalities, hypotonia, neurocognitive impairment, cardiac malformations and increased cancer risks.…”

Section: Introductionmentioning

confidence: 99%

A Progeroid Syndrome Caused by RAF1 deficiency Underscores the importance of RTK signaling for Human Development

Wong

Tan

TAN

et al. 2022

Preprint

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Somatic and germline gain-of-function point mutations in RAF, the first oncogene to be discovered in humans, delineate a group of tumor-prone syndromes known as RASopathies. In this study, we document the first human phenotype resulting from the germline loss of function of the proto-oncogene RAF1 (a.k.a. CRAF). In a consanguineous family, we uncovered a homozygous p.Thr543Met mutation segregating with a neonatal lethal progeroid syndrome with cutaneous, craniofacial, cardiac and limb anomalies. Structure-based prediction and functional tests using human knock-in cells showed that threonine 543 is essential to: 1) ensure RAF1s stability and phosphorylation, 2) maintain its kinase activity towards substrates of the MAPK pathway and 3) protect from stress-induced apoptosis. When injected in Xenopus embryos mutant RAF1T543M failed to phenocopy the effects of overactive FGF/MAPK signaling confirming its hypomorphic activity. Collectively, our data disclose the genetic and molecular etiology of a novel segmental progeroid syndrome which highlights the importance of RTK signaling for human development and homeostasis.

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SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype

Cited by 38 publications

References 80 publications

The RASopathies: from pathogenetics to therapeutics

The RASopathies: from pathogenetics to therapeutics

The seventh international RASopathies symposium: Pathways to a cure—expanding knowledge, enhancing research, and therapeutic discovery

A Progeroid Syndrome Caused by RAF1 deficiency Underscores the importance of RTK signaling for Human Development

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