Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Frings mice are a model of generalized epilepsy and have seizures in response to loud noises. This phenotype is due to the autosomal recessive inheritance of a single gene on mouse chromosome 13. Here we report the fine genetic and physical mapping of the locus. Sequencing of the region led to identification of a novel gene; mutant mice are homozygous for a single base pair deletion that leads to premature termination of the encoded protein. Interestingly, the mRNA levels of this gene in various tissues are so low that the cDNA has eluded detection by standard library screening approaches. Study of the MASS1 protein will lead to new insights into regulation of neuronal excitability and a new pathway through which dysfunction can lead to epilepsy.
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PMID:A novel gene causing a mendelian audiogenic mouse epilepsy. 1154 6

Until recently, all genes found to be mutated in hereditary idiopathic epilepsies encoded subunits of ion channels, leading to the view of this class of diseases as channelopathies. Two apparent exceptions to this rule are the MASS1 gene, which is mutated in the Frings mouse model of audiogenic epilepsy, and the LGI1 gene, which is mutated in autosomal dominant partial epilepsy with auditory features (ADPEAF). Careful sequence analysis of the two protein products encoded by those genes shows a common feature: both sequences harbour a novel homology domain consisting of a 7-fold repeated 44-residue motif. The architecture and structural features of this new domain make it a likely member of the growing class of protein interaction domains with a seven-bladed beta-propeller fold. In the MASS1 gene product, which has recently been shown to be a fragment of the very large G-protein-coupled receptor VLGR1, this EAR domain (for epilepsy-associated repeat) is part of the ligand-binding ectodomain. LGI1, as well as a number of newly identified LGI1 relatives, is predicted to be a secreted protein, and consists of an N-terminal leucine-rich repeat region and a C-terminal EAR region. The known portion of the human genome encodes six EAR proteins, some of which map to chromosome regions associated with seizure disorders. The EAR domain is likely to play an important role in the pathogenesis of epilepsy, either by binding to an unknown anti-epileptic ligand, or more likely by interfering with axon guidance or synaptogenesis.
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PMID:A common protein interaction domain links two recently identified epilepsy genes. 1209 17

A naturally occurring mutation of the mass1 (monogenic audiogenic seizure-susceptible) gene recently has been reported in the Frings mouse strain, which is prone to audiogenic seizures. The human orthologous gene, MASS1, was mapped to chromosome 5q14, for which we previously have reported significant evidence of linkage to febrile seizures (FEB4). We screened for MASS1 mutations in individuals from 48 families with familial febrile seizures and found 25 DNA alterations. None of nine missense polymorphic alleles was significantly associated with febrile seizures; however, a nonsense mutation (S2652X) causing a deletion of the C-terminal 126 amino acid residues was identified in one family with febrile and afebrile seizures. Our results suggest that a loss-of-function mutation in MASS1 might be responsible for the seizure phenotypes, though it is not likely that MASS1 contributed to the cause of febrile seizures in most of our families.
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PMID:A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures. 1240 66

Usher syndrome type II (USH2) is a genetically heterogeneous autosomal recessive disorder with at least three genetic subtypes (USH2A, USH2B, and USH2C) and is classified phenotypically as congenital hearing loss and progressive retinitis pigmentosa. The VLGR1 (MASS1) gene in the 5q14.3-q21.1 USH2C locus was considered a likely candidate on the basis of its protein motif structure and expressed-sequence-tag representation from both cochlear and retinal subtracted libraries. Denaturing high-performance liquid chromatography and direct sequencing of polymerase-chain-reaction products amplified from 10 genetically independent patients with USH2C and 156 other patients with USH2 identified four isoform-specific VLGR1 mutations (Q2301X, I2906FS, M2931FS, and T6244X) from three families with USH2C, as well as two sporadic cases. All patients with VLGR1 mutations are female, a significant deviation from random expectations. The ligand(s) for the VLGR1 protein is unknown, but on the basis of its potential extracellular and intracellular protein-protein interaction domains and its wide mRNA expression profile, it is probable that VLGR1 serves diverse cellular and signaling processes. VLGR1 mutations have been previously identified in both humans and mice and are associated with a reflex-seizure phenotype in both species. The identification of additional VLGR1 mutations to test whether a phenotype/genotype correlation exists, akin to that shown for other Usher syndrome disease genes, is warranted.
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PMID:Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type II. 1474 Mar 21

A genetic aetiology is estimated to be present in about 40% of patients with epilepsy. Significant progress has been made in understanding the molecular genetic basis of Mendelian epilepsies. Fourteen genes have been identified which underlie a group of rare, autosomal dominant Mendelian idiopathic epilepsies. All but two of these genes encode subunits of ion-channels, revealing that idiopathic Mendelian human epilepsies are predominantly channelopathies. The two non-ion-channel genes, LGl1 causing autosomal dominant lateral temporal lobe epilepsy and MASS1 causing febrile and afebrile seizures, both contain a novel repeat motif variously called the epilepsy-associated repeat (EAR) and epitempin (EPTP) repeat. This motif defines a subfamily of genes, some of which have also been implicated in epilepsy in mice and humans. Progress in dissecting the more common 'complex' genetic epilepsies remains slow, but ion channels represent the most biologically plausible candidates. Characterization of common population sequence variants for the entire cohort of ion channel genes and the development of high-throughput techniques should enable rapid advances in the understanding of the common idiopathic familial epilepsies.
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PMID:Molecular basis of Mendelian idiopathic epilepsies. 1511 29

The Frings mouse is a model of audiogenic seizure (AGS) susceptibility. The genetic locus responsible for the AGS phenotype in the Frings mouse has been named monogenic audiogenic seizure-susceptible (MASS1). MASS1 is unique in that it is one of only two identified seizure loci that are not associated with an ion channel mutation. Furthermore, Frings mice display a robust AGS phenotype demonstrating very high and prolonged susceptibility to sound-induced tonic extension seizures. The purpose of this investigation was to use c-Fos immunohistochemistry to map the brain structures involved in the Frings AGS and to examine neuronal hyperexcitability in the inferior colliculus, the brain structure that is recognized as the site of AGS initiation. AGS mapping revealed that intense seizure-induced neuronal activation was mostly limited to structures involved in a brainstem seizure network, including the external and dorsal nuclei of the inferior colliculus, as observed in other AGS rodents. Acoustically induced c-Fos expression in the central nucleus of the inferior colliculus to sub-AGS threshold tone stimulations displayed a greater level of neuronal activation in AGS-susceptible Frings, DBA/2J and noise-primed C57BL/6J mice compared to AGS-resistant C57BL/6J and CF1 mice. The AGS-susceptible mice also displayed c-Fos immunoreactivity that was more focused within the tonotopic response domain of the inferior colliculus compared to AGS-resistant mice. Furthermore, Frings mice displayed significantly greater tonotopic hyper-responsiveness compared to other AGS-susceptible mice.
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PMID:c-Fos immunohistochemical mapping of the audiogenic seizure network and tonotopic neuronal hyperexcitability in the inferior colliculus of the Frings mouse. 1551 28

Febrile seizures (FS) represent the most common seizure disorder in childhood and contribution of a genetic predisposition has been clearly proven. In some families FS is associated with a wide variety of afebrile seizures. Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a spectrum of phenotypes including FS, atypical febrile seizures (FS+) and afebrile generalized and partial seizures. Mutations in the genes SCN1B, SCN1A and GABRG2 were identified in GEFS+ families. GEFS+ is genetically heterogeneous and mutations in these three genes were detected in only a minority of the families. We performed a 10 cM density genome-wide scan in a multigenerational family with febrile seizures and epilepsy and obtained a maximal multipoint LOD score of 3.12 with markers on chromosome 5q14.3-q23.1. Fine mapping and segregation analysis defined a genetic interval of approximately 33 cM between D5S2103 and D5S1975. This candidate region overlapped with a previously reported locus for febrile seizures (FEB4) in the Japanese population, in which MASS1 was proposed as disease gene. Mutation analysis of the exons and exon-intron boundaries of MASS1 in our family did not reveal a disease causing mutation. Our linkage data confirm for the first time that a locus on chromosome 5q14-q23 plays a role in idiopathic epilepsies. However, our mutation data is negative and do not support a role for MASS1 suggesting that another gene within or near the FEB4 locus might exist.
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PMID:Genome-wide linkage of febrile seizures and epilepsy to the FEB4 locus at 5q14.3-q23.1 and no MASS1 mutation. 1627 91

Molecular karyotyping is being increasingly applied to delineate novel disease causing microaberrations and related syndromes in patients with mental retardation of unknown aetiology. We report on three unrelated patients with overlapping de novo interstitial microdeletions involving 5q14.3-q15. All three patients presented with severe psychomotor retardation, epilepsy or febrile seizures, muscular hypotonia and variable brain and minor anomalies. Molecular karyotyping revealed three overlapping microdeletions measuring 5.7, 3.9 and 3.6 Mb, respectively. The microdeletions were identified using single nucleotide polymorphism (SNP) arrays (Affymetrix 100K and Illumina 550K) and array comparative genomic hybridization (1 Mb Sanger array-CGH). Confirmation and segregation studies were performed using fluorescence in situ hybridization (FISH) and quantitative PCR. All three aberrations were confirmed and proven to have occurred de novo. The boundaries and sizes of the deletions in the three patients were different, but an overlapping region of around 1.6 Mb in 5q14.3 was defined. It included five genes: CETN3, AC093510.2, POLR3G, LYSMD3 and the proximal part of GPR98/MASS1, a known epilepsy gene. Haploinsufficiency of GPR98/MASS1 is probably responsible for the seizure phenotype in our patients. At least one other gene contained in the commonly deleted region, LYSMD3, shows a high level of central nervous expression during embryogenesis and is also, therefore, a good candidate gene for other central nervous system (CNS) symptoms, such as psychomotor retardation, brain anomalies and muscular hypotonia of the 5q14.3 microdeletion syndrome.
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PMID:A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients. 1947 18

An 18-year-old female with mild mental disability (global IQ 69), febrile seizures with subsequent myoclonic/grand mal epilepsy, and subtle morphologic changes is described with del 5(q14.3q21.3) by karyotype and minimal DNA deletion of 21.08 Mb by array comparative genomic hybridization microarray analysis (arr chr5:83,592,798-104,671,993 X1) that encompasses at least 50 genes. Included in the deletion interval is the MEF2C gene that usually causes severe mental disability when haploinsufficient, illustrating the complexity of clinic-cytogenetic correlation even with defined segmental aneuploidy. Interaction of MEF2C with the deleted febrile seizure (FEB4) and juveline myoclonic epilepsy (EJM4) loci plus the G-protein receptor (GPR98/MASS1/Usher syndrome) gene may moderate the phenotype, perhaps through common regulation by calcium.
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PMID:Interstitial deletion 5q14.3q21.3 with MEF2C haploinsufficiency and mild phenotype: when more is less. 2156 30

The very large G protein-coupled receptor 1 (VLGRI), also known as MASS1 or GPR98, is most notable among the family of adhesion-GPCR for its size. Encoded by an 18.9 kb open reading frame, the approximately 700 kDa primary translation product is by far the largest GPCR and additionally, the largest cell surface protein known to date. The large ectodomain of the protein contains several repeated motifs, including some 35 calcium binding, Calx-beta repeats and seven copies of an epitempin repeat thought to be associated with the development of epilepsy. The extreme carboxy-terminus contains a consensus PDZ ligand sequence, suggesting interactions with other cytosolic or cytoskeletal proteins. At least two spontaneous and two targeted mutant mouse lines are currently known. The mutant mice present with sensitivity to audiogenic seizures but also have cochlear defects and significant, progressive hearing impairment. Although its ligand is currently unknown, VLGR1 is one of the few adhesion-GPCR family members in which mutations have been shown to be responsible for a human malady. Mutations in VLGRI in humans result in one form (2C) of Usher syndrome, the most common genetic cause of combined blindness and deafness.
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PMID:Studies on the very large G protein-coupled receptor: from initial discovery to determining its role in sensorineural deafness in higher animals. 2161 27


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