Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy

Morante‐Redolat, José Manuel; Gorostidi-Pagola, Ana; Sirerol-Piquer, María Salomé; Sáenz, Amets; Poza, Juan José; Galán, Juan Carlos; Gesk, Stefan; Sarafidou, Theologia; Mautner, Victor; Binelli, S.; Staub, Eike; Hinzmann, Bernd; French, Lisa; Prud’homme, Jean François; Passarelli, D.; Scannapieco, Paolo; Tassinari, C. A.; Avanzini, G.; Martí-Massó, J.F.; Kluwe, Lan; Deloukas, Panos; Moschonas, Nicholas Κ.; Michelucci, Roberto; Siebert, Reiner; Nobile, Carlo; Pérez‐Tur, Jordi; Munáin, Adolfo López de

doi:10.1093/hmg/11.9.1119

Cited by 303 publications

(236 citation statements)

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“…Interestingly, further evidence for the disease relevance of these proteins come from known genetic variations. Human LGI1-mutations produce a lateral temporal lobe epilepsy syndrome 17 and mice lacking LGI1 show a variety of motor semiologies 18 . Humans with CASPR2 mutations present autism, seizures, and peripheral neuropathy 19 .…”

Section: The Vgkc-complex: Lgi1 Caspr2 and Contactin-2mentioning

confidence: 99%

The expanding spectrum of clinically-distinctive, immunotherapy-responsive autoimmune encephalopathies

Irani

Vincent

2012

Arq. Neuro-Psiquiatr.

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The autoimmune encephalopathies are a group of conditions that are associated with autoantibodies against surface neuronal proteins, which are likely to mediate the disease. They are established as a frequent cause of encephalitis. Characteristic clinical features in individual patients often allow the specificity of the underlying antibody to be confidently predicted. Antibodies against the VGKC-complex, mainly LGI1(leucine-rich glioma-inactivated 1), CASPR2 (contactin-associated protein 2), and contactin-2, and NMDA (N-methyl, D-aspartate) -receptor are the most frequently established serological associations. In the minority of cases, an underlying tumour can be responsible. Early administration of immunotherapies, and tumour removal, where it is relevant, offer the greatest chance of improvement. Prolonged courses of immunotherapies may be required, and clinical improvements often correlate well with the antibody levels. In the present article, we have summarised recent developments in the clinical and laboratory findings within this rapidly expanding field.

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Section: The Vgkc-complex: Lgi1 Caspr2 and Contactin-2mentioning

confidence: 99%

The expanding spectrum of clinically-distinctive, immunotherapy-responsive autoimmune encephalopathies

Irani

Vincent

2012

Arq. Neuro-Psiquiatr.

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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: Introductionmentioning

confidence: 99%

“…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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“…2,3 Its inheritance pattern is autosomal dominant with reduced penetrance (around 70%). Mutations associated with ADLTE are found in leucine-rich, glioma inactivated 1 (LGI1 [MIM: 604619]) [4][5][6] in 30%-50% of ADLTE-affected families. 3,7,8 Other genes harboring ADLTE-causing mutations are unknown.…”

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confidence: 99%

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

Dazzo

Fanciulli²,

Serioli

et al. 2015

The American Journal of Human Genetics

107

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Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.Temporal-lobe epilepsy is the most common type of focal epilepsy. It is sometimes associated with structural brain lesions, but genetic forms have also been described. Familial temporal-lobe epilepsy comprises two genetically distinct syndromes: familial mesial temporal-lobe epilepsy (FMTLE [MIM: 611630]) 1 and autosomal-dominant lateral temporal epilepsy (ADLTE [MIM: 600512]), also named autosomal-dominant partial epilepsy with auditory features (ADPEAF). 2 ADLTE is a well-defined epileptic syndrome clinically characterized by focal seizures with prominent auditory and/or aphasic symptoms, normal brain MRI, and relatively benign evolution. 2,3 Its inheritance pattern is autosomal dominant with reduced penetrance (around 70%). Mutations associated with ADLTE are found in leucine-rich, glioma inactivated 1 (LGI1 [MIM: 604619]) 4-6 in 30%-50% of ADLTE-affected families. 3,7,8 Other genes harboring ADLTE-causing mutations are unknown.LGI1 is expressed mainly in neurons, particularly in the neocortex and limbic regions, 4,9 and its protein product, LGI1, is secreted. 9 LGI1 has been implicated in the transmission of K þ and AMPA synaptic currents 10,11 and in the regulation of post-natal maturation of cortical excitatory synapses and dendrite pruning. 12 However, it is not known which of these functions underlies ADLTE. Identification of additional genes whose mutations cause ADLTE will help to clarify the pathoge...

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Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy

Cited by 303 publications

References 16 publications

The expanding spectrum of clinically-distinctive, immunotherapy-responsive autoimmune encephalopathies

The expanding spectrum of clinically-distinctive, immunotherapy-responsive autoimmune encephalopathies

LGI1mutations in autosomal dominant and sporadic lateral temporal epilepsy

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

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