Legius syndrome in fourteen families

Denayer, Ellen; Chmara, Magdalena; Brems, Hilde; Kievit, Anneke; Bever, Yolande van; Ouweland, Ans M.W. van den; Minkelen, Rick van; Goede-Bolder, Arja de; Oostenbrink, Rianne; Lakeman, Phillis; Beert, Eline; Ishizaki, Takuma; Mori, Tomoaki; Keymolen, Kathelijn; Ende, Jenneke van den; Mangold, Elisabeth; Peltonen, Sirkku; Brice, Glen; Rankin, Julia; Spaendonck‐Zwarts, Karin Y. van; Yoshimura, Akihiko; Legius, Eric

doi:10.1002/humu.21404

Cited by 45 publications

(40 citation statements)

References 18 publications

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“…The majority of reported Spred1 mutations produce a premature stop codon, resulting in C-terminally truncated protein products (Brems et al 2007;Messiaen et al 2009;Pasmant et al 2009;Spurlock et al 2009;Muram-Zborovski et al 2010;Denayer et al 2011;Laycock-van Spyk et al 2011;Spencer et al 2011). As the SPR domain has previously been reported to target Spred1 to the plasma membrane via interactions with phospholipids and caveolin-1 (Lim et al 2002;Nonami et al 2005), we surmised that the truncated mutants were unable to function as a result of mislocalization.…”

Section: Resultsmentioning

confidence: 97%

“…Thus far, ;12 missense mutations in SPRED1 have been characterized as pathogenic in Legius syndrome (11 point mutations and one four-amino-acid in-frame deletion), five of which are used in this study (Supplemental Table S1; Brems et al 2007;Messiaen et al 2009;Pasmant et al 2009;Spurlock et al 2009;Denayer et al 2011;Spencer et al 2011). Of these 12 missense mutations, nine localize to the EVH1 domain.…”

Section: Resultsmentioning

confidence: 99%

“…Initial experiments revealed that Spred1 mutations were loss-of-function mutations, incapable of inhibiting the Ras/MAPK pathway (Brems et al 2007). SPRED1 mutations account for at least 2% of the pathogenic mutations associated with patients clinically diagnosed with NF1 (Brems et al 2007;Messiaen et al 2009;Pasmant et al 2009;Spurlock et al 2009;Muram-Zborovski et al 2010;Denayer et al 2011;Laycock-van Spyk et al 2011;Spencer et al 2011).…”

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confidence: 99%

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A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1

Stowe

Mercado²,

Stowe³

et al. 2012

Genes Dev.

130

148

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The Ras/mitogen-activated protein kinase (MAPK) pathway plays a critical role in transducing mitogenic signals from receptor tyrosine kinases. Loss-of-function mutations in one feedback regulator of Ras/MAPK signaling, SPRED1 (Sprouty-related protein with an EVH1 domain), cause Legius syndrome, an autosomal dominant human disorder that resembles Neurofibromatosis-1 (NF1). Spred1 functions as a negative regulator of the Ras/MAPK pathway; however, the underlying molecular mechanism is poorly understood. Here we show that neurofibromin, the NF1 gene product, is a Spred1-interacting protein that is necessary for Spred1's inhibitory function. We show that Spred1 binding induces the plasma membrane localization of NF1, which subsequently down-regulates Ras-GTP levels. This novel mechanism for the regulation of neurofibromin provides a molecular bridge for understanding the overlapping pathophysiology of NF1 and Legius syndrome.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1

Stowe

Mercado²,

Stowe³

et al. 2012

Genes Dev.

130

148

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“…Patient SPRED1 cDNA-SPRED1 mutation analysis was performed at the Department of Human Genetics, Catholic University of Leuven, Belgium, and in the UAB Medical Genomics Laboratory, University of Alabama at Birmingham, in individuals with a Legius syndrome phenotype (19). Some samples were sent by clinical geneticists from other centers.…”

Section: Methodsmentioning

confidence: 99%

Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1

Hirata

Brems

Suzuki

et al. 2016

Journal of Biological Chemistry

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Constitutional heterozygous loss-of-function mutations in the SPRED1 gene cause a phenotype known as Legius syndrome, which consists of symptoms of multiple café-au-lait macules, axillary freckling, learning disabilities, and macrocephaly. Legius syndrome resembles a mild neurofibromatosis type 1 (NF1) phenotype. It has been demonstrated that SPRED1 functions as a negative regulator of the Ras-ERK pathway and interacts with neurofibromin, the NF1 gene product. However, the molecular details of this interaction and the effects of the mutations identified in Legius syndrome and NF1 on this interaction have not yet been investigated. In this study, using a yeast two-hybrid system and an immunoprecipitation assay in HEK293 cells, we found that the SPRED1 EVH1 domain interacts with the N-terminal 16 amino acids and the C-terminal 20 amino acids of the GTPase-activating protein (GAP)-related domain (GRD) of neurofibromin, which form two crossing ␣-helix coils outside the GAP domain. These regions have been shown to be dispensable for GAP activity and are not present in p120 GAP . Several mutations in these N-and C-terminal regions of the GRD in NF1 patients and pathogenic missense mutations in the EVH1 domain of SPRED1 in Legius syndrome reduced the binding affinity between the EVH1 domain and the GRD. EVH1 domain mutations with reduced binding to the GRD also disrupted the ERK suppression activity of SPRED1. These data clearly demonstrate that SPRED1 inhibits the Ras-ERK pathway by recruiting neurofibromin to Ras through the EVH1-GRD interaction, and this study also provides molecular basis for the pathogenic mutations of NF1 and Legius syndrome.Spred (Sprouty-related protein with an EVH1 domain) family proteins, initially discovered as c-Kit-and c-Fms-binding proteins, have been shown to suppress the Ras-ERK pathway. Spreds form a subfamily of the Sprouty/Spred family, which is characterized by the Sprouty-related C-terminal cysteine-rich (SPR) 3 domain. In mammals, four Sprouty homologues and three members of the Spred family of proteins, Spred1, Spred2, and Spred3, have been discovered. Mammalian Spreds can negatively regulate the Ras-Raf-ERK pathway (1, 2); however, compared with Spred1 and Spred2, Spred3 has much weaker ERK suppression activity (3). The SPR domain has been shown to be palmitoylated, causing Sprouty and Spred to localize in the membrane fraction (4, 5). Spred1 and Spred2 are composed of an N-terminal enabled/vasodilator-stimulated protein homology 1 (EVH1) domain, a central c-Kit-binding domain, and a cysteine-rich C-terminal SPR domain, whereas Spred3 lacks a functional c-Kit-binding domain.

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“…9 In addition, heterozygous loss-offunction mutations in another gene, SPRED1, have been described to cause NF1-like disease associated with CALS and inguinal/axillary freckles but no neurofibromas or Lisch nodules (Legius syndrome (MIM# #611431)). 10,11 Similarly to neurofibromin, SPRED1 is a negative regulator of RAS-MAPK signaling. 12 Before the cloning of the NF1 gene two other related disorders, Watson syndrome (WS) and NF1-Noonan syndrome (NFNS), had been described clinically, both have been shown to be caused by NF1 mutations.…”

Section: Introductionmentioning

confidence: 99%

Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype–phenotype correlation

et al. 2012

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Neurofibromatosis type 1 (NF1) and its related disorders (NF1-Noonan syndrome (NFNS) and Watson syndrome (WS)) are caused by heterozygous mutations in the NF1 gene. Pulmonary stenosis (PS) occurs more commonly in NF1 and its related disorders than in the general population. This study investigated whether PS is associated with specific types of NF1 gene mutations in NF1, NFNS and WS. The frequency of different NF1 mutation types in a cohort of published and unpublished cases with NF1/NFNS/WS and PS was examined. Compared with NF1 in general, NFNS patients had higher rates of PS (9/35 ¼ 26% vs 25/2322 ¼ 1.1%, P valueo0.001). Stratification according to mutation type showed that the increased PS rate appears to be driven by the NFNS group with non-truncating mutations. Eight of twelve (66.7%) NFNS cases with non-truncating mutations had PS compared with a 1.1% PS frequency in NF1 in general (Po0.001); there was no increase in the frequency of PS in NFNS patients with truncating mutations. Eight out of eleven (73%) individuals with NF1 and PS, were found to have non-truncating mutations, a much higher frequency than the 19% reported in NF1 cohorts (Po0.015). Only three cases of WS have been published with intragenic mutations, two of three had non-truncating mutations. Therefore, PS in NF1 and its related disorders is clearly associated with non-truncating mutations in the NF1 gene providing a new genotype-phenotype correlation. The data indicate a specific role of non-truncating mutations on the NF1 cardiac phenotype.

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Legius syndrome in fourteen families

Cited by 45 publications

References 18 publications

A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1

A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1

Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1

Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype–phenotype correlation

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