Mutations in
            <i>LZTR1</i>
            add to the complex heterogeneity of schwannomatosis

Smith, Miriam J.; Isidor, B.; Beetz, Christian; Williams, Simon G.; Bhaskar, Sanjeev S.; Richer, Wilfrid; O’Sullivan, James; Anderson, Beverly L.; Daly, Sarah B.; Urquhart, Jill; Fryer, Alan; Rustad, Cecilie F.; Mills, Samantha J.; Samii, Amir; Plessis, Daniel du; Halliday, Dorothy; Barbarot, S.; Bourdeaut, Franck; Newman, William G.; Evans, D. Gareth

doi:10.1212/wnl.0000000000001129

Cited by 92 publications

(103 citation statements)

References 21 publications

(18 reference statements)

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“…Meningiomas can also be found in about 5% of the patients [40]. Schwannomatosis is genetically distinct from NF2, but clinical distinction can be challenging as some of the schwannomatosis patients fulfil the NF2 diagnostic criteria [26,41].…”

Section: Schwannomatosismentioning

confidence: 99%

“…In the original publication, Pitrowski et al claimed that LZTR1 germline mutations could be found in 80% of schwannomatosis patients lacking germline mutations in SMARCB1 [47]. These numbers have been challenged by two independent groups claiming that LZTR1 are responsible for approximately 20% of the sporadic cases [41,51]. Hence, it is likely that there are additional schwannomatosis causing genes on chromosome 22q.…”

Section: Lztr1mentioning

confidence: 99%

“…Hence, it is likely that there are additional schwannomatosis causing genes on chromosome 22q. Interestingly, Smith et al reported on four patients with LZTR1 germline mutations that had unilateral vestibular schwannomas plus at least one other schwannoma [41]. In contrast, there are no reports of vestibular schwannomas in schwannomatosis patients with SMARCB1 germline mutations and the presence of these tumors have previously been considered an exclusion criteria for schwannomatosis [41].…”

Section: Lztr1mentioning

confidence: 99%

“…Interestingly, Smith et al reported on four patients with LZTR1 germline mutations that had unilateral vestibular schwannomas plus at least one other schwannoma [41]. In contrast, there are no reports of vestibular schwannomas in schwannomatosis patients with SMARCB1 germline mutations and the presence of these tumors have previously been considered an exclusion criteria for schwannomatosis [41]. Hence, schwannomatosis and NF2 are genetically distinct disorders with overlapping symptoms that could in some cases complicate the diagnostic distinction between these two disorders.…”

Section: Lztr1mentioning

confidence: 99%

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Recent developments in brain tumor predisposing syndromes

2015

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Section: Schwannomatosismentioning

confidence: 99%

Section: Lztr1mentioning

confidence: 99%

Section: Lztr1mentioning

confidence: 99%

Section: Lztr1mentioning

confidence: 99%

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Recent developments in brain tumor predisposing syndromes

2015

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“…The implication of LZTR1 in human disease was first reported with the DiGeorge Syndrome, as it was deleted in the majority of DiGeorge Syndrome patients [13]. More recently, somatic mutations with loss of heterozygosity in LZTR1 and germline loss-of-function variants in LZTR1 were respectively associated with glioblastoma multiforme [14] and schwannomatosis [15,16].…”

Section: Discussionmentioning

confidence: 99%

Further Evidence for the Implication of LZTR1, a Gene not Associated with the Ras-Mapk Pathway, in the Pathogenesis of Noonan Syndrome

Ghedira¹,

Kraoua²,

Lagarde³

et al. 2017

Biol Med

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Molecular Genetics of Schwannomatosis

Hulsebos

2017

Encyclopedia of Life Sciences

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Schwannomatosis is characterised by the development of multiple schwannomas, and in some cases meningiomas, but without the involvement of bilateral vestibular schwannomas, the latter being the hallmark of neurofibromatosis type 2 (NF2). Severe pain is the most important clinical symptom in patients. Germ line mutations in SMARCB1 or LZTR1 on chromosome 22 predispose to the development of schwannomas in schwannomatosis. These genes explain 86% of the familial but only 40% of the sporadic cases. Independent somatic mutations in NF2 , which is also on chromosome 22, are found in the schwannomas of patients, but not in their germ line. Most mutations in SMARCB1 are hypomorphic mutations, giving rise to a SMARCB1 protein with modified activity. Many mutations in LZTR1 are loss‐of‐function mutations, resulting in the absence of LZTR1 protein. Unilateral vestibular schwannomas may occur in LZTR1 ‐associated schwannomatosis. Overlap exists of the clinical symptoms of schwannomatosis and mosaic NF2. Comprehensive testing of the genes involved in blood and tumours of the patient may help in the clinical diagnosis of schwannomatosis. Identification of additional genes and pathways involved should be performed to identify possible targets for therapy and relief of pain. Key Concepts Schwannomatosis patients develop multiple schwannomatosis, but not bilateral vestibular schwannomas, the latter being characteristic for neurofibromatosis type 2 (NF2). Pain is the most important clinical symptom in schwannomatosis. It often persists after removal of the schwannoma. The tumour suppressor genes SMARCB1 and LZTR1 are predisposing genes in schwannomatosis. These genes explain many, but not all, sporadic and familial cases. Most germ line SMARCB1 mutations in schwannomatosis are hypomorphic mutations, resulting in the synthesis of a protein with modified activity. Many germ line LZTR1 mutations are loss‐of‐function mutations, resulting in the absence of protein. Independent somatically acquired NF2 mutations are found in the multiple schwannomas of schwannomatosis patients. Unilateral vestibular schwannoma may occur in LZTR1 ‐associated schwannomatosis. Bilateral vestibular schwannomas have not been reported in schwannomatosis patients. The similarities in clinical phenotype between schwannomatosis and mosaic NF2 may cause diagnostic confusion.

show abstract

Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis

Cited by 92 publications

References 21 publications

Recent developments in brain tumor predisposing syndromes

Recent developments in brain tumor predisposing syndromes

Further Evidence for the Implication of LZTR1, a Gene not Associated with the Ras-Mapk Pathway, in the Pathogenesis of Noonan Syndrome

Molecular Genetics of Schwannomatosis

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