Coexistence of schwannomatosis and glioblastoma in two families

Deiller, Caroline; Van-Gils, Julien; Zordan, Cécile; Tinat, Julie; Loiseau, Hugues; Fabre, Thierry; Delleci, C.; Cohen, Jérémy E.; Vidaud, Michel; Parfait, Béatrice; Goizet, Cyril

doi:10.1016/j.ejmg.2019.103680

Cited by 12 publications

(13 citation statements)

References 14 publications

(22 reference statements)

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“…This protein binds to the N-terminal domain of CUL3 via the BTB-BACK domain and to substrates via the KELCH domain (15). Mutations in LZTR1 are also identified in Noonan syndrome (18)(19)(20) and schwannomatosis (21)(22)(23)(24). Noonan syndrome is the most common RASopathy caused by mutations in genes involved in the RAS/MAPK signaling pathway, whereas schwannomatosis is a rare neurofibromatosis.…”

Section: Introductionmentioning

confidence: 99%

LZTR1 inactivation promotes MAPK/ ERK pathway activation in glioblastoma by stabilizing oncoprotein RIT1

Wang

Zhang

et al. 2020

Preprint

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Large-scale sequencing studies on glioblastoma have identified numerous genetic alterations.Leucine-zipper-like transcription regulator 1 (LZTR1) is inactivated by non-synonymous mutations and copy number losses, suggesting that it is a tumor suppressor in glioblastoma.However, how LZTR1 mutations contribute to glioblastoma pathogenesis remains poorly understood. Here, we revealed that LZTR1, as an adaptor of the CUL3 E3 ubiquitin ligase complex, recognizes and triggers ubiquitin-dependent degradation of oncoprotein RIT1, a RAS-like GTPase. Wild-type LZTR1 suppresses glioblastoma cell proliferation and migration by inactivating the MAPK/ERK signaling pathway in a RIT1-dependent manner. However, the effects were abrogated by the glioblastoma-associated LZTR1 mutations. Our findings revealed the underlying molecular mechanism of LZTR1 mutations-driven glioblastoma, and provide novel therapeutic target for LZTR1 mutations-driven glioblastoma.

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Section: Introductionmentioning

confidence: 99%

LZTR1 inactivation promotes MAPK/ ERK pathway activation in glioblastoma by stabilizing oncoprotein RIT1

Wang

Zhang

et al. 2020

Preprint

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“…However, recently, pathogenic variants in LZTR1 have also been involved in a small proportion of patients with Noonan syndrome, a rare neurodevelopmental syndrome [ 42 ] either in a dominant or in a recessive fashion of transmission; it has been postulated that dominant negative missense variant cause the dominant form and hypomorphic in trans with loss-of-function variants are at the base of the recessive one. Moreover, a recurrent mixed glioma tumor of oligoastrocytoma type was described in such a patient [ 43 ] and coexistence of schwannomatosis and glioblastoma in two families [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Simultaneous Detection of NF1, SPRED1, LZTR1, and NF2 Gene Mutations by Targeted NGS in an Italian Cohort of Suspected NF1 Patients

Bianchessi

Ibba

Saletti

et al. 2020

Genes

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Neurofibromatosis type 1 (NF1) displays overlapping phenotypes with other neurocutaneous diseases such as Legius Syndrome. Here, we present results obtained using a next generation sequencing (NGS) panel including NF1, NF2, SPRED1, SMARCB1, and LZTR1 genes on Ion Torrent. Together with NGS, the Multiplex Ligation-Dependent Probe Amplification Analysis (MLPA) method was performed to rule out large deletions/duplications in NF1 gene; we validated the MLPA/NGS approach using Sanger sequencing on DNA or RNA of both positive and negative samples. In our cohort, a pathogenic variant was found in 175 patients; the pathogenic variant was observed in NF1 gene in 168 cases. A SPRED1 pathogenic variant was also found in one child and in a one year old boy, both NF2 and LZTR1 pathogenic variants were observed; in addition, we identified five LZTR1 pathogenic variants in three children and two adults. Six NF1 pathogenic variants, that the NGS analysis failed to identify, were detected on RNA by Sanger. NGS allows the identification of novel mutations in five genes in the same sequencing run, permitting unambiguous recognition of disorders with overlapping phenotypes with NF1 and facilitating genetic counseling and a personalized follow-up.

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“…The endogenous and exogenous expression of wild-type LZTR1 displays punctate endomembrane immunostaining, but diffuse and uniform cytoplasmic staining when LZTR1 mutations occur in the BACK domains, including in the Leu812Pro mutant ( 58 ). Interestingly, unlike NS- and GBM-associated LZTR1 mutations, which are concentrated in the Kelch domains, schwannomatosis-associated LZTR1 mutations are more evenly distributed across all domains, and these mutations may result in failure to bind with CUL3 ( 38 , 39 , 46 – 48 ). In summary, disease-related LZTR1 mutations are defective in mediating substrate ubiquitination by disrupting the formation of substrate-LZTR1-CUL3 complexes ( Fig.…”

Section: Structure and Mutations Of The Lztr1 Proteinmentioning

confidence: 99%

“…However, unlike other BTB-Kelch proteins, LZTR1 shows no interaction with actin but is localized on the Golgi complex ( 40 ), suggesting a unique function and status. Mutations in the LZTR1 gene occur in ≤8% of patients with NS ( 46 , 47 ), 4.4% of those with GBM ( 39 , 48 ) and 24.4% of those with schwannomatosis ( Table I ) ( 49 – 51 ). The occurrence of these diseases is related to abnormal function of RAS proteins, demonstrating a close relationship between LZTR1 and proteins of the RAS superfamily ( 38 , 52 – 54 ).…”

Section: Introductionmentioning

confidence: 99%

LZTR1: A promising adaptor of the CUL3 family (Review)

et al. 2021

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The study of the disorders of ubiquitin-mediated proteasomal degradation may unravel the molecular basis of human diseases, such as cancer (prostate cancer, lung cancer and liver cancer, etc.) and nervous system disease (Parkinson's disease, Alzheimer's disease and Huntington's disease, etc.) and help in the design of new therapeutic methods. Leucine zipper-like transcription regulator 1 (LZTR1) is an important substrate recognition subunit of cullin-RING E3 ligase that plays an important role in the regulation of cellular functions. Mutations in LZTR1 and dysregulation of associated downstream signaling pathways contribute to the pathogenesis of Noonan syndrome (NS), glioblastoma and chronic myeloid leukemia. Understanding the molecular mechanism of the normal function of LZTR1 is thus critical for its eventual therapeutic targeting. In the present review, the structure and function of LZTR1 are described. Moreover, recent advances in the current knowledge of the functions of LZTR1 in NS, glioblastoma (GBM), chronic myeloid leukemia (CML) and schwannomatosis and the influence of LZTR1 mutations are also discussed, providing insight into how LZTR1 may be targeted for therapeutic purposes.

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Coexistence of schwannomatosis and glioblastoma in two families

Cited by 12 publications

References 14 publications

LZTR1 inactivation promotes MAPK/ ERK pathway activation in glioblastoma by stabilizing oncoprotein RIT1

LZTR1 inactivation promotes MAPK/ ERK pathway activation in glioblastoma by stabilizing oncoprotein RIT1

Simultaneous Detection of NF1, SPRED1, LZTR1, and NF2 Gene Mutations by Targeted NGS in an Italian Cohort of Suspected NF1 Patients

LZTR1: A promising adaptor of the CUL3 family (Review)

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