A second paroxysmal kinesigenic choreoathetosis locus (EKD2) mapping on 16q13-q22.1 indicates a family of genes which give rise to paroxysmal disorders on human chromosome 16

Valente, Enza Maria; Spacey, Sian; Wali, Gautam; Bhatia, Kailash P.; Dixon, Peter H.; Wood, Nicholas W.; Davis, Mary B.

doi:10.1093/brain/123.10.2040

Cited by 116 publications

(70 citation statements)

References 22 publications

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“…This PKC-critical region (PKCCR) was confirmed by others (Bennett et al 2000;Swoboda et al 2000;Valente et al 2000;CuencaLeon et al 2002). In addition, mapped regions for other conditions probably allelic to PKC, such as infantile convulsions and paroxysmal choreoathetosis (ICCA; MIM 602066) and benign familial infantile convulsions (BFIC2; MIM 605751), shared with that for PKC (Lee et al 1998;Hattori et al 2000;Swoboda et al 2000;Caraballo et al 2001;Weber et al 2004).…”

Section: Introductionsupporting

confidence: 53%

“…Since all of these loci were confined to a relatively small region, it is likely that all of these paroxysmal movement dis- Fig. 4 The PKC-critical region (PKCCR) summarized by five mapping studies (Tomita et al 1999;Bennett et al 2000;Swoboda et al 2000;Cuenca-Leon et al 2002, present study), as well as a seemingly second PKC locus (EKD2) by Valente et al (2000). The location of markers and intermarker distances are from the Gé né thon map (Dib et al 1996) orders actually belong to one disorder and are allelic, as suggested previously (Tomita et al 1999).…”

Section: Discussionmentioning

confidence: 80%

“…Thus, the shortest region of overlap (SRO) did not become narrower than a 12.4-cM segment detected by Tomita et al (1999). Valente et al (2000) assigned a form of PKC (a second PKC locus, EKD2), in an Indian family, to a segment between D16S416 and D16S503, the region distinct from those mapped by Tomita et al (1999) and by Swoboda et al (2000). Furthermore, two other clinical entities, ICCA and BFIC2, were assigned to a region encompassing the centromere of chromosome 16 (Lee et al 1998;Hattori et al 2000;Swoboda et al 2000;Caraballo et al 2001;Weber et al 2004).…”

Section: Discussionmentioning

confidence: 81%

“…Some neurologists consider PKC as a form of reflex epilepsy, whereas others believe that basal ganglia dysfunction may play a role in its cause (Kato et al 2006). Most (40-70%) were familial cases in which PKC was transmitted in an autosomal dominant mode of inheritance with incomplete penetrance (Tomita et al 1999;Valente et al 2000). Males are affected more often than females, with an estimated ratio of 3-4:1 (Bhatia 1999).…”

Section: Introductionmentioning

confidence: 99%

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Paroxysmal kinesigenic choreoathetosis (PKC): confirmation of linkage to 16p11-q21, but unsuccessful detection of mutations among 157 genes at the PKC-critical region in seven PKC families

et al. 2007

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Paroxysmal kinesigenic choreoathetosis (PKC) is a paroxysmal movement disorder of unknown cause. Although the PKC-critical region (PKCCR) has been assigned to the pericentromeric region of chromosome 16 by several studies of families from various ethnic backgrounds, the causative gene has not yet been identified. In the present study, we performed linkage and haplotype analysis in four new families with PKC, as well as an intensive polymerase chain reaction (PCR) based mutation analysis in seven families for a total of 1,563 exons from 157 genes mapped around the PKCCR. Consequently, the linkage/haplotype analysis revealed that PKC was assigned to a 24-cM segment between D16S3131 and D16S408, the result confirming the previously defined PKCCR, but being unable to narrow it down. Although the mutation analysis of the 157 genes was unsuccessful at identifying any mutations that were shared by patients from the seven families, two nonsynonymous substitutions, i.e., 6186C>A in exon 3 of SCNN1G and 45842A>G in exon 29 of ITGAL, which were segregated with the disease in Families C and F, respectively, were not observed in more than 400 normal controls. Thus, one of the two genes, SCNN1G and ITGAL, could be causative for PKC, but we were not able to find any other mutations that explain the PKC phenotype.

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Section: Introductionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

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Paroxysmal kinesigenic choreoathetosis (PKC): confirmation of linkage to 16p11-q21, but unsuccessful detection of mutations among 157 genes at the PKC-critical region in seven PKC families

et al. 2007

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“…The intervals for ICCA, BFIE and PKC/PKD from 13 published studies are shown in Figure 3. Two of these localisations (Valente et al, 2000;Callenbach et al, 2005) are small and do not overlap, suggesting that there may be more than one causative gene in the region. However, most of the localisations are large and span the centromere, a region of greatly reduced recombination on chromosome 16, especially in female meioses.…”

Section: The Chromosome 16p112-q121 Bfie Locusmentioning

confidence: 99%

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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Molecular Genetics of the Paroxysmal Dyskinesias

Kaiyrzhanov

Houlden²

2017

Encyclopedia of Life Sciences

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Paroxysmal or episodic neurological disorders are frequent in the population and include many common conditions such as migraine, epilepsy and movement disorders. Paroxysmal movement disorders are particularly heterogeneous and difficult to accurately diagnose, but the identification of many new genes and the advent of genetic testing have improved accuracy significantly. Many disease genes in paroxysmal disorders are critical to synaptic function, particularly at the presynaptic terminal where defects in a number of genes that are channels, involved in vesicle release and neurotransmitter receptors have been identified. Key Concepts Paroxysmal dyskinesias are clinically complex and often difficult to define. The genotype–phenotype correlations are not reliable. Paroxysmal dyskinesias are different from channelopathies. The major genes are PRRT2, SLC2A1 and MR1. Multigene diagnostic panels should be used in genetic analysis.

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A second paroxysmal kinesigenic choreoathetosis locus (EKD2) mapping on 16q13-q22.1 indicates a family of genes which give rise to paroxysmal disorders on human chromosome 16

Cited by 116 publications

References 22 publications

Paroxysmal kinesigenic choreoathetosis (PKC): confirmation of linkage to 16p11-q21, but unsuccessful detection of mutations among 157 genes at the PKC-critical region in seven PKC families

Paroxysmal kinesigenic choreoathetosis (PKC): confirmation of linkage to 16p11-q21, but unsuccessful detection of mutations among 157 genes at the PKC-critical region in seven PKC families

The Molecular Genetics of the Benign Epilepsies of Infancy

Molecular Genetics of the Paroxysmal Dyskinesias

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