DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for LZTR1-related schwannomatosis — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleLZTR1-related schwannomatosis maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for lztr1-related schwannomatosis is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
leucine zipper like post translational regulator 1 (LZTR1) — LZTR1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet gdpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9MEZ · 2.8 Å · ligand GUANOSINE-5'-DIPHOSPHATE (GDP). Experimental structure, not a prediction.
What the evidence adds up to
Mutations in LZTR1 are found in 37.5% of familial schwannomatosis cases (6 of 16 patients with at least one affected relative) and 22% of sporadic cases (11 of 49 patients) in a cohort of 65 unrelated individuals who were negative for NF2 or SMARCB1 mutations. Among 39 patients with a unilateral vestibular schwannoma plus at least one other schwannoma, 2 had germline LZTR1 mutations. Three germline mutation-positive patients in total developed a unilateral vestibular schwannoma. The frequency of loss-of-function LZTR1 variants in schwannomatosis probands is 17.8% (64 of 359), significantly higher than the 0.36% frequency of potential loss-of-function variants in the general population. However, the presence of many loss-of-function LZTR1 variants in people without clinical symptoms of schwannomatosis suggests that LZTR1 variants confer a reduced risk of schwannomas compared to germline NF2 or SMARCB1 pathogenic variants, and incomplete penetrance makes classification of novel variants challenging.
Germline mutations in SMARCB1 or LZTR1 on chromosome 22 explain 86% of familial but only 40% of sporadic schwannomatosis cases. Most SMARCB1 mutations are hypomorphic, producing a protein with modified activity, while many LZTR1 mutations are loss-of-function, resulting in absence of the protein. Independent somatic mutations in NF2, also on chromosome 22, are found in schwannomas from patients but not in their germline. A somatic 5-hit/3-step mechanism involving loss of function of LZTR1 and contiguous genes on 22q11.2q12.2 has been described. Two families have been reported in which LZTR1-related schwannomatosis segregated with glioblastoma: in one, the proband's father died of an apparently isolated glioblastoma at age 59; in the other, the proband's sister died of a lethal glioblastoma at age 78, and both glioblastoma samples carried the familial LZTR1 mutation.
Pain is the most important clinical symptom and often persists after surgical removal of schwannomas. Treatment is conservative if asymptomatic and surgical if symptomatic, with the goal of symptom control and preservation of neurological function. There are currently no drug therapies for schwannomatosis. Schwannomas are difficult to treat because surgery involves cutting affected nerves, and there is a paucity of cell cultures and cell lines, resulting in a lack of molecular and cell biology data. A study of 20 tumors found several mutations but did not identify a drug target.
What is still missing is a clear understanding of the additional causative genes that must exist for the 60% of sporadic cases not explained by SMARCB1 or LZTR1. There are no cell lines or animal models adequate for drug screening, no funded clinical trials for any pharmacological intervention, and no patient stratification strategy beyond genetic testing for the known genes. The observation of glioblastoma in two families with LZTR1 mutations is based on only two cases and requires replication in larger cohorts before it can inform any therapeutic approach.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neurology · 2014 · 124 citations · open access
Mutations in <i>LZTR1</i> add to the complex heterogeneity of schwannomatosis
AbstractOBJECTIVES: We aimed to determine the proportion of individuals in our schwannomatosis cohort whose disease is associated with an LZTR1 mutation. METHODS: We used exome sequencing, Sanger sequencing, and copy number analysis to screen 65 unrelated individuals with schwannomatosis who were negative for a germline NF2 or SMARCB1 mutation. We also screened samples from 39 patients with a unilateral vestibular schwannoma (UVS), plus at least one other schwannoma, but who did not have an identifiable germline or mosaic NF2 mutation. RESULTS: We identified germline LZTR1 mutations in 6 of 16 patients (37.5%) with schwannomatosis who had at least one affected relative, 11 of 49 (22%) sporadic patients, and 2 of 39 patients with UVS in our cohort. Three germline mutation-positive patients in total had developed a UVS. Mosaicism was excluded in 3 patients without germline mutation in NF2, SMARCB1, or LZTR1 by mutation screening in 2 tumors from each. CONCLUSIONS: Our data confirm the relationship between mutations in LZTR1 and schwannomatosis. They indicate that germline mutations in LZTR1 confer an increased risk of vestibular schwannoma, providing further overlap with NF2, and that further causative genes for schwannomatosis remain to be identified.
British Journal of Neurosurgery · 2020 · 46 citations · open access
What to know about schwannomatosis: a literature review
AbstractBACKGROUND: Schwannomatosis is a relatively rare disorder and is related to neurofibromatosis type 2. Although there is clinical overlap between schwannomatosis and neurofibromatosis type 2, these diseases have to be regarded as separate entities due to the genetic origin and course of the disease. METHODS: A comprehensive review of the literature was conducted for relevant studies using Pubmed and Cochrane databases to discuss the epidemiology, clinical presentation, diagnostic criteria, pathological and imaging features, treatment and genetics of schwannomatosis. RESULTS: gene play a role in the pathophysiology of schwannomatosis. The most common symptom is pain with affection of the spine and peripheral nerves in the majority of patients. High quality contrast enhanced MRI scan is the imaging modality of choice. Treatment is conservative if asymptomatic and surgical if symptomatic. The goal is symptom control with preservation of neurological function. CONCLUSION: Schwannomatosis is a relatively rare disorder in which the main goal is to preserve neurological function.
Human Mutation · 2022 · 14 citations · open access
Comparison of the frequency of loss‐of‐function <i>LZTR1</i> variants between schwannomatosis patients and the general population
AbstractSchwannomatosis is a rare tumor predisposition syndrome that causes multiple schwannomas. Germline loss-of-function (LoF) LZTR1 variants were only recently identified as disease-causing, so relatively few variants have been identified in patients. In addition, many LoF variants exist in Genome Aggregation Database (gnomAD) in people who do not have clinical symptoms of schwannomatosis. These factors, and the incomplete penetrance seen in this condition, hinder definitive interpretation of the clinical significance of novel LoF variants identified in schwannomatosis patients. We collated published LOF LZTR1 variants identified in schwannomatosis patients and classified them according to current American College of Medical Genetics and Genomics/Association for Molecular Pathology/Association of Clinical Genomic Science guidelines. Subsequently, pathogenic/likely pathogenic schwannomatosis-associated LoF variants were compared with LoF LZTR1 variants reported in gnomAD data. Using current classification guidelines, 64/71 LoF LZTR1 variants reported in schwannomatosis patients in the literature were classified as pathogenic/likely pathogenic, and their frequency in probands 64/359 (17.8%) was significantly higher than the frequency of potential LoF variants identified in the general population (0.36%; p < 0.0001). The majority of published classifications of schwannomatosis-associated LoF variants are robust. However, the high frequency of LoF LZTR1 variants in the general population suggests that LZTR1 variants confer a reduced risk of schwannomas compared to germline NF2 and SMARCB1 pathogenic variants, making classification of novel variants challenging.
Encyclopedia of Life Sciences · 2017 · 0 citations
Molecular Genetics of Schwannomatosis
AbstractAbstract 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.
UF Journal of Undergraduate Research · 2019 · 0 citations · open access
Molecular Studies of Candidate Gene Somatic Mutations in Human Schwannoma Tumors
AbstractSchwannomas are benign Schwann cell tumors on the peripheral nerves that occur in the autosomal dominant conditions of NF2 (neurofibromatosis type 2) or schwannomatosis. NF2 is caused by germline mutations in the NF2 gene, and patients can form tumors when the remaining normal gene copy is mutated. In schwannomatosis, two genes are known to have germline mutations: SMARCB1 and LZTR1, both near the NF2 gene on chromosome 22. Schwannomas in schwannomatosis have variable somatic deletions of multiple genes, and the tumors also have a risk of becoming malignant. These tumors can cause deformities, functional problems, substantial pain, and even lead to death. Schwannomas are difficult to treat because surgery involves cutting the affected nerves. There are currently no drug therapies, and due to the paucity of cell cultures and cell lines, there is a lack of molecular and cell biology data about schwannomas. The goal of this work was to better characterize a set of 20 tumors, to contribute information helpful in developing more targeted therapies. This involved loss of heterozygosity study using polymorphisms in or near the genes NF2, LZTR1 and SMARCB1 to identify somatic deletions. DNA sequencing of SMARCB1 exons was also carried out to search for germline and somatic mutations. This work revealed several mutations that contribute new knowledge to the field.
European Journal of Medical Genetics · 2010 · 0 citations
Considerações sobre auditoria interna e controles internos em instituições financeiras
AbstractSchwannomatosis is a rare affection predisposing to multiple peripheral neurologic tumors development. Approximatively, one third of patients with schwannomatosis are carriers of a germline mutation in LZTR1 (Leucin Zipper Transcription Regulator 1). Tumorigenesis in schwannomatosis responds to a somatic 5-hit/3-step mechanism resulting in a loss of function (LOF) of LZTR1 and the contiguous genes of locus 22q11.2q12.2. Effectively, LZTR1 is mapped on 22q11.2 and centromeric to SMARCB1 also implicated in the determinism of schwannomatosis and NF2, responsible for neurofibromatosis type 2. On a somatic point of view, LZTR1 mutations are known to drive with a significant frequency glioblastoma (GB) development. We report here two families in which segregate both multiple schwannomas and GB. In the first family, the proband received a diagnosis with of schwannomatosis after a surgery for a lumbar schwannoma at age 43, molecularly confirmed by identification of a germline heterozygous mutation in LZTR1. Her father, having unremarkable medical history deceased from an apparently isolated GB at age 59. In the second family, LZTR1-related schwannomatosis was diagnosed in the index case at age 70 after multiple schwannomas surgeries. Her elder sister had no neurological medical history before occurrence of a lethal GB at age 78. Molecular analysis of GB sample from both affected relatives showed the presence of the familial mutation. These observations hypothesize a potential link between schwannomatosis and the GB development.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
