KChannelDB: Extraction of mutation data from the literature

This data was extracted from Medline abstracts and full texts (when available) in an automated manner.

The table below describes the selected point mutation and provides links to other documents. The sentence(s) where the point mutation R83H was found are listed after the table.

The mutated residues are also indicated in the family sequence alignments and hyperlinked to the corresponding mutation pages.

Point mutation R83H in KCNE3_HUMAN

Relevant sentences:

R83H

• Alert me when: new articles cite this article Download to Citation Manager Collections under which this article appears: Muscle disease Ion channel gene defects Neurology 2003 ; 61:857-859 © 2003 American Academy of Neurology ------------------------------------------------------------------------ Brief Com munications Lack of association of the potassium channel-associated peptide MiRP2-R83H variant with periodic paralysis D

• (image)References A missense variant (R83H) of the gene (KCNE3) encoding a potassium channel-associated peptide , MinK-related peptide 2 (MiRP2) , has been reported in periodic paralysis patients

• In the current study , no difference in the frequency of the MiRP2-R83H variant between periodic paralysis patients and healthy individuals was found

• These observations weaken the proposal that MiRP2-R83H causes periodic paralysis

• Andersen’s syndrome is another form of dominant periodic paralysis associated with cardiac and dysmorphic signs and is due to missense or in-frame deletions of the KCNJ2 inwardly rectifying potassium channel gene.4 A missense variant in the KCNE3 gene encoding MinK-related peptide 2 (MiRP2) , a potassium channel-associated peptide , was reported in 2 of 100 independent cases with periodic paralysis.5 A transition from G to A was identified at position 340 of KCNE3 mRNA , predicting an arginine-to-histidine amino acid substitution at position 83 of MiRP2 peptide (MiRP2-R83H variant)

• In a distinct study , 1 patient of 15 with thyrotoxic hypoPP carried the MiRP2-R83H variant.6 These reports suggested that the MiRP2-R83H variant caused hereditary periodic paralyses and predisposed to thyrotoxic hypoPP

• Following up these observations , we studied the frequency of the MiRP2-R83H variant in patients with periodic paralysis and in a large group of 506 healthy control subjects

• (image)References We estimated the frequency of the MiRP2-R83H variant in a large group of periodic paralysis patients , using SSCP or DHPLC screening techniques

• This patient belonged to Subgroup B (hypoPP with SCN4A mutations) and carried both MiRP2-R83H variant and SCN4A-R672H mutation , which causes hypoPP2 (figure )

• Given this result , we screened available members of this family for both MiRP2-R83H and SCN4A-R672H

• We found that the affected father carried the SCN4A-R672H mutation , whereas the healthy mother carried the MiRP2-R83H variant (see the figure )

• It is worth noting that the severity of the disease (duration and frequency of the attacks) was comparable between father (carrying SCN4A-R672H) and son (carrying both SCN4A-R672H and MirP2-R83H)

• In Subgroup A (hypoPP or hyperPP patients with no SCN4A or CACNA1S mutation) , none of the patients presented the MiRP2-R83H variant

• In the group of healthy controls (Group 2) , 8 of 506 healthy individuals carried the MirP2-R83H , yielding a frequency of 0.0158

• Altogether , our data indicate that the frequency of MiRP2-R83H variant obtained in patients with periodic paralysis (0.0096) is not different from that observed in healthy control subjects (0.0158) (see the table )

• View this table: [in this window] [in a new window]   Table 1 Frequency of MiRP2-R83H variant in periodic paralysis patients and in healthy controls View larger version (31K): [in this window] [in a new window]   Figure

• Healthy mother carries a potassium channel-associated peptide KCNE3-R83H variant (R83H+ / -)

• The son is a double heterozygote for SCN4A-R672H and KCNE3-R83H (arrow)

• SCN4A-R672H is inherited from the father and KCNE3-R83H from the mother

• (B) Single-strand conformational polymorphism analysis profiles of PCR-amplified SCN4A exon 12 region (a: patient [R672H] ; b: control) and KCNE3 3' coding region (a': patient [R83H] ; b': control)

• (image)References This study demonstrates that the frequency of the MiRP2-R83H variant obtained from patients with periodic paralysis is comparable with that obtained from a large group of healthy control subjects

• It is noteworthy that the only patient carrying MiRP2-R83H variant also carried a well-characterized hypoPP2 SCN4A mutation

• In contrast to MiRP2-R83H variant , this hypoPP2 SCN4A variant clearly segregated with the disease

• Altogether , our results argue against a causative role of the MiRP2-R83H variant in periodic paralyses

• In the original report , the MiRP2-R83H variant was associated with either hyperPP- or hypoPP-like phenotypes , 5 which weakens the hypothesized causative link between genotype and phenotype

• Indeed , up to now , approximately 30 missense mutations in the SCN4A and 3 in the CACNA1S genes have been described , and none of them has been linked to both phenotypes.1 , 2 One may therefore not exclude that , alike our SCN4A-R672H patient , patients reported by Abbott and et al5 carry , in addition to MiRP2-R83H variant , other distinct hyperPP or hypoPP mutations that remained unidentified despite the efforts of the authors

• In the same study , the authors investigated the functional consequences of MiRP2-R83H in heterologous expression systems.5 They hypothesized that MiRP2 operates with Kv3.4 potassium channels in skeletal muscle to set the resting membrane potential and that MiRP2-R83H variant may alter this function when co-expressed with wild-type MiRP2

• However , a further and more direct confirmation of MiRP2 role in skeletal muscle is needed , as conflicting expression data have been reported for KCNE3.5 , 7 MiRP2 may indeed interact with different potassium channel subunits , as it has been suggested for MiRP1 in heart.8-10 The in vivo pathophysiologic relevance of the functional abnormalities induced by MiRP2-R83H when co-expressed in vitro with Kv3.4 needs , therefore , further evaluation before this variant can be classified as a risk factor for muscle excitability diseases

F.Horn (kchanneldbcmbi.ru.nl), 17-Aug-2005