A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors

Chernova, Olga B.; Somerville, Robert; Cowell, John K.

doi:10.1038/sj.onc.1202481

Cited by 175 publications

(180 citation statements)

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“…Although a single transmembrane domain was initially predicted in its central part [Chernova et al, 1998], the Lgi1 protein does not contain any transmembrane domain and is therefore thought to be secreted [Morante-Redolat et al, 2002;Staub et al, 2002]. This view is supported by in vitro experiments that have shown that the Lgi1 protein produced by transfected cells is secreted into the cell medium [Furlan et al, 2006;Senechal et al, 2005].…”

Section: Introductionsupporting

confidence: 57%

“…The LGI1 gene was cloned in 1998 due to its rearrangements in the T98G glioblastoma multiforme cell line, and was found to be downregulated in many malignant gliomas, suggesting a possible tumor suppressor function [Chernova et al, 1998]. However, neither point mutations affecting the LGI1 coding sequence nor differential methylation of its core promoter region could be demonstrated in these tumors, arguing against a role of LGI1 as a tumor suppressor gene [Krex et al, 2002;Piepoli et al, 2006;Somerville et al, 2000].…”

Section: Introductionmentioning

confidence: 99%

“…LGI1 is expressed mainly in the brain and to a lesser degree in skeletal muscle [Chernova et al, 1998]. In both tissues, two mRNA isoforms resulting from alternative splicing are present: a fulllength 2254-bp transcript, which is more abundantly expressed in the brain, and a shorter splice isoform of 1456 bp, encompassing the 5 0 half of the full-length coding region, which is expressed at lower levels [Chernova et al, 1998;Morante-Redolat et al, 2002].…”

Section: Introductionmentioning

confidence: 99%

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LGI1mutations in autosomal dominant and sporadic lateral temporal epilepsy

et al. 2009

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Autosomal dominant lateral temporal epilepsy (ADLTE) or autosomal dominant partial epilepsy with auditory features (ADPEAF) is an inherited epileptic syndrome with onset in childhood/adolescence and benign evolution. The hallmark of the syndrome consists of typical auditory auras or ictal aphasia in most affected family members. ADTLE/ADPEAF is associated in about half of the families with mutations of the leucine-rich, glioma-inactivated 1 (LGI1) gene. In addition, de novo LGI1 mutations are found in about 2% of sporadic cases with idiopathic partial epilepsy with auditory features, who are clinically similar to the majority of patients with ADLTE/ADPEAF but have no family history. Twenty-five LGI1 mutations have been described in familial and sporadic lateral temporal epilepsy patients. The mutations are distributed throughout the gene and are mostly missense mutations occurring in both the N-terminal leucine rich repeat (LRR) and C-terminal EPTP (beta propeller) protein domains. We show a tridimensional model of the LRR protein region that allows missense mutations of this region to be divided into two distinct groups: structural and functional mutations. Frameshift, nonsense and splice site point mutations have also been reported that result in protein truncation or internal deletion. The various types of mutations are associated with a rather homogeneous phenotype, and no obvious genotypephenotype correlation can be identified. Both truncating and missense mutations appear to prevent secretion of mutant proteins, suggesting a loss of function effect of mutations. The function of LGI1 is unclear. Several molecular mechanisms possibly leading to lateral temporal epilepsy are illustrated and briefly discussed.

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Section: Introductionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LGI1mutations in autosomal dominant and sporadic lateral temporal epilepsy

et al. 2009

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“…Chernova et al 8 were the first to describe LGI1, upon observing that the gene was disrupted by translocation in the T98G glioblastoma multiforme (GBM) cell line and in over one-quarter of primary tumors. LGI1 expression is absent or significantly downregulated in many highgrade but not low-grade gliomas, suggesting a role for LGI1 in glial tumor progression 8,9 .…”

Section: )mentioning

confidence: 99%

“…A detailed clinical description of each family has been presented separately 2,3,7 . 8,9 . Beginning at the amino terminus (left), the protein contained a predicted signal peptide (filled arrow; positions , an N-terminal cysteine-rich LRR flanking sequence (LRRNT; residues 45-71), three LRR repeat sequences (orange boxes; residues 90-113, 114-137 and 138-161), a C-terminal cysteine-rich LRR flanking sequence (LRRCT; residues 173-222), two direct repeat sequences (Rep1 and 2; residues 226-361 and 420-549, respectively) and a putative membrane-spanning segment (yellow rectangle).…”

Section: Urlsmentioning

confidence: 99%

Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features

et al. 2002

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The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures 1 . Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances 2,3 . We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes ( Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of LGI1 promotes glial tumor progression. We show that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies.Correspondence should be addressed to R.O. (e-mail: ro6@columbia.edu). NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2008 December 22. Published in final edited form as:Nat Genet. 2002 March ; 30(3): 335-341. doi:10.1038/ng832. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn 1995 we mapped the ADPEAF locus to a 10-cM region on chromosome 10q24 in a single extended pedigree 2 . Linkage was subsequently reported to an overlapping interval in another large family, narrowing the minimal genetic region to approximately 3 cM, assuming the causative gene was the same 4 . Analysis of additional pedigrees confirmed the linkage but failed to narrow the region further 5-7 . To screen for disease-related mutations, we resequenced all coding-exon and bordering-intron sequences from positional candidate genes in the overlap interval in one affected individual from each of three ADPEAF pedigrees showing linkage to chromosome 10q24 (families 6610, A and B; Fig. 2) 2,7 . We then genotyped putative diseaserelated mutations in all available family members from the three linked pedigrees, all family members from two smaller families with ADPEAF (families C and D; Fig. 2) and 123 unrelated control individuals.Resequencing of LGI1 identified presumptive mutations in each of the five families with ADPEAF (Table 1 and Fig. 2). All tested affected individuals from the five families harbored a single copy of a putative disease mutation, as did all obligate carriers and individuals classified as 'unknown' who were found to carry the disease-linked haplotype (Fig. 2). Several unaffected individuals also carried the disease haplotype and presumptive mutation. Whether these individuals manifest subclinical signs of disease or have undergone recent changes in affection status is not yet known, but the results are consistent with our previous estimate of 71% disease-gene penetrance in family 6610 (ref.2).To di...

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Darts in the Dark Cure Animal, but Not Human, Brain Tumors

Fathallah‐Shaykh¹

2002

Arch Neurol

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A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors

Cited by 175 publications

References 25 publications

LGI1mutations in autosomal dominant and sporadic lateral temporal epilepsy

LGI1mutations in autosomal dominant and sporadic lateral temporal epilepsy

Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features

Darts in the Dark Cure Animal, but Not Human, Brain Tumors

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