Confirmation of linkage of benign familial neonatal convulsions to D20S19 and D20S20

Malafosse, Alain; Leboyer, Marion; Dulac, Olivier; Navelet, Y; Plouin, Perrine; Beck, Corinne; Laklou, Hassan; Mouchnino, G; Grandscene, Pierre; Vallée, Louis; Guilloud-Bataille, M; Samolyk, D; Baldy-Moulinier, M; Feingold, Josué; Mallet, Jacques

doi:10.1007/bf00207042

Cited by 78 publications

(26 citation statements)

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“…[14]. Another marker, D20S19, has been localized adjacent to D20S20 and D20S24 and is tightly linked to the three brain-specific phenotypes benign familial neonatal convulsions (BFNC) [15,16], low-voltage EEG (LVEEG) [17] and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) [18]. ADNFLE is a partial epilepsy which typically begins in childhood and leads to clusters of brief seizures during light sleep or drowsing [19].…”

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confidence: 99%

An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics

et al. 1996

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The ¢z4 subunit of the neuronal nicotinic acetylcholine receptor is the first gene shown to be involved in a human idiopathic epileptic disease. A missense mutation, leading to the replacement of serine 248 by phenylalanine in the second transmembrane segment, had been detected in patients with autosomal dominant nocturnal frontal lobe epilepsy. The properties of the wild type receptor composed of ~4 and ~2 subunits and the mutant receptor where ¢z4 subunits carried the mutation at serine 248 were compared by means of cDNA manipulation and expression in Xenopus oocytes. The mutant receptor exhibited faster desensitization upon activation by acetylcholine and recovery from the desensitized state was much slower than in the wild type receptor. We conclude that the reported mutation causes seizures via a diminution of the activity of the ¢x4[~2 neuronal nicotinic acetylcholine receptor.

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Section: Introductionmentioning

confidence: 99%

An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics

et al. 1996

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“…Linkage has now been established for some of the generalized human epileptic syndromes. In benign familial nenonatal convulsions (BFNCs), the EBNl and EBN2 genes have been mapped to chromosomes 20q and 8q (3)(4)(5). Linkage was reported for EPMR (Northern epilepsy syndrome) on chromosome 8p (6), and the gene (EPM1) for Unverricht-Lundborg disease has been localized to chromosome 21q (7).…”

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Occurrence of Epilepsies in Family Members of Indian Probands with Different Epileptic Syndromes

et al. 1997

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Summary:Purpose: Large numbers of families with many members having seizures have been used to understand the role of hereditary factors in the pathogenesis of human epileptic syndromes. We aimed to establish a genetic database to form a hypothesis on the possible genetic contributions in different epileptic syndromes.Methods: The occurrence and patterns of different epilepsies and epileptic syndromes in 1,219 Indian probands and their relatives were studied. The concordance of epilepsies between probands and relatives was also analyzed.Results: Of probands, 231 (19% of 1219) had first-or second-degree relatives affected with seizures. Incidence of family history in probands with generalized epilepsies (GES) and syndrome of single, small, enhancing lesions (SSEL) was comparable and significantly higher than that in probands with localization-related epilepsies (LRES). The ratio of affected first-to second-degree relatives was close to 4: 1. Generalized epilepsies were the commonest type of epileptic syndromes seen among all relatives. The proportion of sibs and seconddegree relatives with epileptic syndromes similar to probands was significantly greater in the GES group as compared with the concordant relatives of probands with LRES and SSEL.Conclusions: A significant percentage of first-and seconddegree relatives of probands with all types of epileptic syndromes have seizures. The risk of relatives being affected varied as a function of the relation with the proband. Concordance of epileptic syndromes between probands and relatives was related to the epileptic syndromes in probands. The syndrome of SSEL is probably a benign epileptic syndrome seen in Indians genetically predisposed to seizures. Hereditary factors may play an almost equal role in the predisposition of relatives to epilepsy in families of probands with different epileptic syndromes.

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“…BFNE was originally mapped to the KCNQ2 locus in 1989 (Leppert et al) by linkage analysis of a large, four-generation pedigree. Further families were reported that confirmed the chromosome 20q localisation (Ryan et al, 1991;Malafosse et al, 1992). KCNQ2 was identified as the BFNE gene at this locus when a submicroscopic deletion containing KCNQ2 was detected in a single BFNE family.…”

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The Molecular Genetics of the Benign Epilepsies of Infancy

Heron¹,

Mulley²

2011

Clinical and Genetic Aspects of Epilepsy

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Clinical and Genetic Aspects of Epilepsy 96 overlaps with BFNE and BFIE. Seizure onset in BFNIE most commonly occurs at between 2 and 4 months of age. Clinically the condition was first described by Kaplan and Lacey (1983) and molecularly delineated two decades later (Heron et al., 2002). The aim of this chapter is to describe the current state of knowledge of the molecular genetics underlying these disorders and the significance that this has for patient care. The molecular genetics of benign familial neonatal epilepsyBenign familial neonatal epilepsy is most commonly caused by mutations in two related voltage-gated potassium channel subunit genes, KCNQ2 and KCNQ3. Together, these form the pore of the neuronal M-channel, which plays an important role in neuronal inhibition by acting as a "brake" on repetitive action potential discharges (Delmas & Brown, 2005). Mutations in KCNQ2 and KCNQ3 were originally described in 1998 (Biervert et al., 1998;Charlier et al., 1998;Singh et al., 1998). There are now more than 80 known mutations in KCNQ2; but only four described for KCNQ3. There may be other, rare, families with mutations in other genes. BFNE caused by mutations in the potassium channel subunit KCNQ2KCNQ2 (OMIM 602235) encodes one of the pore-forming subunits of the M-channel. The Mchannel is a heteromultimer consisting of two KCNQ2 and two KCNQ3 proteins, as well as accessory subunits. The gene is located close to the q-arm telomere of chromosome 20, at 20q13.3. It consists of 17 exons embedded within 87kb of genomic DNA. The gene codes for an 872 amino acid protein consisting of three domains: a short N-terminal domain; a transmembrane domain; and a large C-terminal domain, which contains regions that interact with other channel subunits. The gene has five splice variants, which produce proteins that differ in the C-terminal domains. The transmembrane domain consists of six transmembrane segments (S1-S6) and the pore-loop between segments S5 and S6, which forms the lining of the ion pore. The S4 domain is the voltage sensor and contains a number of positively charged arginine or lysine residues, which are required for normal channel function. The S4 segments move within the membrane in response to a change in voltage, opening the channel. BFNE was originally mapped to the KCNQ2 locus in 1989 (Leppert et al.) by linkage analysis of a large, four-generation pedigree. Further families were reported that confirmed the chromosome 20q localisation (Ryan et al., 1991;Malafosse et al., 1992). KCNQ2 was identified as the BFNE gene at this locus when a submicroscopic deletion containing KCNQ2 was detected in a single BFNE family. Screening of additional BFNE families revealed missense, frameshift and splice-site mutations in KCNQ2 . A frameshift mutation was simultaneously identified in KCNQ2 when it was screened as a candidate gene in another family mapped to the 20q locus (Biervert et al., 1998). In total, 85 mutations in KCNQ2 have been described in the scientific literature Soldovieri et al., 2007;Wuttke et al., 2...

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Confirmation of linkage of benign familial neonatal convulsions to D20S19 and D20S20

Cited by 78 publications

References 11 publications

An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics

An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics

Occurrence of Epilepsies in Family Members of Indian Probands with Different Epileptic Syndromes

The Molecular Genetics of the Benign Epilepsies of Infancy

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