* 604433

POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 3; KCNE3


Alternative titles; symbols

MINIMUM POTASSIUM ION CHANNEL-RELATED PEPTIDE 2; MIRP2
MINK-RELATED PEPTIDE 2


HGNC Approved Gene Symbol: KCNE3

Cytogenetic location: 11q13.4     Genomic coordinates (GRCh38): 11:74,454,841-74,467,549 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
11q13.4 ?Brugada syndrome 6 613119 3

TEXT

Cloning and Expression

Abbott et al. (1999) cloned the potassium channel beta subunit KCNE3 by homology to KCNE1 (176261). KCNE3 is a 103-amino acid protein with a relative molecular mass of about 12 kD that displays roughly 35% identity to other KCNE proteins within the single transmembrane domain and a following short stretch. Northern blot analysis revealed a prominent band in the kidney, moderate expression in the small intestine, and weaker bands in most other tissues, including colon and heart. By Northern blot analysis, Abbott et al. (2001) detected KCNE3 mRNA in skeletal muscle, but not in small intestine, colon, kidney, or liver.


Mapping

By radiation hybrid analysis, Abbott et al. (2001) mapped the KCNE3 gene to chromosome 11q13-q14.


Gene Function

When KCNQ1 (607542) interacts with the beta subunit KCNE1, a slow depolarization-activated potassium current I(Ks) is formed that is affected in some forms of cardiac arrhythmia. Schroeder et al. (2000) demonstrated that the beta subunit KCNE3 markedly changes KCNQ1 properties to yield currents that are nearly instantaneous and depend linearly on voltage. KCNE3 also suppresses the currents of KCNQ4 (603537) and HERG (see 152427) potassium channels. In the intestine, KCNQ1 and KCNE3 mRNAs colocalized in crypt cells. This localization, and the pharmacology, voltage dependence, and stimulation by cyclic AMP of KCNQ1/KCNE3 currents, indicated that these proteins may assemble to form the potassium channel that is important for cyclic AMP-stimulated intestinal chloride secretion and that is involved in secretory diarrhea and cystic fibrosis.

In skeletal muscle cells, Abbott et al. (2001) demonstrated that KCNE3 forms stable complexes with the pore-forming unit Kv3.4 (KCNC4; 176265), resulting in potassium channels with increased conductance, faster recovery from inactivation, and slower cumulative inactivation. KCNE3-KCNE4 channels are 80-fold more active at -40 mv and establish the resting membrane potential of skeletal muscle cells. Western blot analysis detected the KCNE3 protein in skeletal muscle plasma membranes.

Melman et al. (2004) showed that KCNE1 and KCNE3 associate with an extended binding interface of KCNQ1 that includes structures within the channel pore and C terminus.


Molecular Genetics

Brugada Syndrome 6

Delpon et al. (2008) sequentially screened 14 ion channel genes in 105 probands with Brugada syndrome (see 601144) and identified a heterozygous mutation in the KCNE3 gene (R99H; 604433.0002) in a proband from a Danish pedigree (Brugada syndrome-6; BRGDA6, 613119). Cotransfection of R99H-mutant KCNE3 with KCNQ1 (607542) produced no alteration in tail current magnitude or kinetics, whereas cotransfection of R99H-mutant KCNE3 with KCND3 (605411) resulted in a significant increase in the transient outward current intensity compared to wildtype. The authors also demonstrated coimmunoprecipitation of Kv4.3 and KCNE3 in human left atrial appendage tissue.

In 40 consecutive Japanese patients with a Brugada-like pattern on electrocardiography, Nakajima et al. (2012) analyzed all coding exons of the SCN5A (600163), SCN1B (600235), SCN3B (608214), KCNE5 (300328), and KCNE3 genes, and identified a 55-year-old man who was heterozygous for a T4A mutation in KCNE3 (604433.0003) and negative for mutation in the other 4 genes as well as in the CACNA1C (114205) and CACNB2 (600003) genes. Functional analysis demonstrated a significantly increased current density with the T4A mutant compared to wildtype.

Possible Role in Periodic Paralysis

Although Abbott et al. (2001) identified an arg83-to-his (R83H; 604433.0001) substitution in 2 of 100 patients with hyperkalemic periodic paralysis (HYPP; 170500) and hypokalemic periodic paralysis (HOKPP; 170400), respectively, Sternberg et al. (2003) and Jurkat-Rott and Lehmann-Horn (2004) concluded that the R83H variant does not play a causative role in periodic paralysis. See 604433.0001 for detailed discussion.

Dias Da Silva et al. (2002) identified the R83H variant in a sporadic case of thyrotoxic periodic paralysis (TPP; 188580). The patient was a 44-year-old Caucasian man of Portuguese descent who had experienced episodic paralysis for 2 years before developing signs of thyrotoxicosis caused by Graves disease (275000). Tang et al. (2004) did not identify the R83H substitution, or any mutations in the KCNE3 gene, among 79 Chinese patients with thyrotoxic hypokalemic periodic paralysis.

Possible Role in Acquired Long QT Syndrome

In 485 Japanese probands with congenital or acquired long QT syndrome (see LQT1, 192500), who on electrocardiography exhibited QT interval prolongation of 460 ms or more or who had documented torsade de pointes, Ohno et al. (2009) analyzed 5 known LQT genes (KCNQ1, 607542; KCNH2, 152427; SCN5A, 600163; KCNE1, 176261; and KCNE2, 603796) as well as the candidate gene KCNE3. A 76-year-old woman with acquired LQT who was negative for mutation in the 5 known LQT genes was found to be heterozygous for the R99H missense mutation in KCNE3 (604433.0002), previously associated with Brugada syndrome. In another 2 unrelated probands with LQT, Ohno et al. (2009) identified a different missense mutation in KCNE3 (T4A; 604433.0003); however, in 1 family, the proband and his asymptomatic mother and sister were also heterozygous for a known LQT-associated variant in the KCNH2 gene (G572S), and electrophysiologic analysis showed that the KCNE3 T4A variant did not have a statistically significant effect on current density.


ALLELIC VARIANTS ( 3 Selected Examples):

.0001 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

KCNE3, ARG83HIS
  
RCV000005879...

This variant, formerly titled HYPOKALEMIC PERIODIC PARALYSIS, HYPERKALEMIC PERIODIC PARALYSIS, and SUSCEPTIBILITY TO THYROTOXIC PERIODIC PARALYSIS based on the findings of Abbott et al. (2001) and Dias Da Silva et al. (2002), has been reclassified based on the findings of Sternberg et al. (2003) and Jurkat-Rott and Lehmann-Horn (2004).

Abbott et al. (2001) identified a 340G-A transition in the KCNE3 gene, resulting in an arg83-to-his (R83H) substitution in 2 of 100 patients with atypical forms of hyperkalemic periodic paralysis (HYPP; 170500) and hypokalemic periodic paralysis (HOKPP; 170400), respectively. However, Sternberg et al. (2003) and Jurkat-Rott and Lehmann-Horn (2004) concluded that the R83H variant does not play a causative role in periodic paralysis and that it is a polymorphism.

Abbott et al. (2001) reported a male proband with atypical HYPP who was negative for mutations in the SCN4A gene and who carried the R83H variant. He presented at 22 months of age with episodic weakness of the extremities. Most episodes came on during sleep and were brief (12 hours), although they occasionally lasted for days. Serum potassium levels during attacks were normal. High carbohydrate meals helped resolve attacks, and treatment with a carbonic anhydrase inhibitor prevented attacks. The age at onset, frequent nature of attacks, and improvement with carbohydrate loading were all consistent with HYPP; however, provocative testing with potassium had not been performed. Frequent attacks upon awakening and absence of myotonia were considered atypical for this diagnosis. Abbott et al. (2001) reported a male proband with atypical HOKPP who was negative for mutations in the SCN4A and CACNA1S genes and who carried the R83H variant. He had onset of episodic paralytic weakness at the age of 14 years. Episodes were characterized by weakness primarily affecting the lower extremities and lasting hours to days, and were usually precipitated by strenuous exercise followed by rest or after prolonged sitting. Carbohydrate ingestion did not precipitate attacks, alcohol intake appeared to facilitate recovery from an attack, and potassium had no effect. He was classified as having hypokalemic periodic paralysis because of the typical age of onset, paralytic attacks that most often occurred after exercise, a low potassium level during a spontaneous attack, and the ability to precipitate an attack with insulin and glucose on 1 occasion. Atypical for this diagnosis was that a second provocative test was negative and that attacks usually occurred while awake. The variant was not found in DNA from a control population of 120 unaffected individuals, suggesting to them that it does not represent a polymorphism.

Abbott et al. (2001) reported functional expression studies that showed that the mutant R83H KCNE3-Kv3.4 complexes exhibited reduced current density and diminished capacity to set resting membrane potential as a dominant-negative effect compared to wildtype. In in vitro studies, Abbott et al. (2006) found that the R83H variant shifts the voltage-dependence of channel activation in response to pH change. The current through the mutant channel decreased compared to wildtype as intracellular pH was lowered. The authors suggested that R83H acts as a regulatory domain, and concluded that the variation may predispose to the development of periodic paralysis.

In contrast, Sternberg et al. (2003) did not identify the R83H mutation in 64 probands with either HYPP or HOKPP in whom mutations in the SCN4A and CACNA1S genes had been excluded. One patient with HOKPP had the R83H change, but he also had a mutation in the SCN4A gene (R672H; 603967.0016). His father, who had the same clinical phenotype and the SCN4A mutation, did not carry the R83H mutation, whereas the asymptomatic mother carried the R83H variant. The findings yielded a frequency of 0.0096 in patients with periodic paralysis (1 in 104) and 0.0158 (8 of 506) in healthy controls. Likewise, Jurkat-Rott and Lehmann-Horn (2004) identified the R83H mutation in 1 of 76 patients with HYPP, in 1 of 61 patients with paramyotonia congenita (608390), in 5 unaffected relatives, in 0 of 8 patients with TTPP, and in 3 of 321 healthy controls, suggesting that it is a polymorphism. Provocation of an unaffected carrier with glucose or potassium administration did not induce weakness. The authors offered a formula for determining causality of a mutation based on reduced penetrance, but concluded that the R83H mutation does not cause these muscle disorders.

Dias Da Silva et al. (2002) identified the R83H substitution in 1 of 15 patients with thyrotoxic hypokalemic periodic paralysis (188580). The patient was a 44-year-old Caucasian man of Portuguese descent who experienced episodic paralysis for 2 years before developing thyrotoxicosis caused by Graves disease (275000). Two of his 3 offspring, all asymptomatic, were found to have the same variant. Tang et al. (2004) did not identify the R83H substitution, or any mutations in the KCNE3 gene, among 79 Chinese patients with thyrotoxic hypokalemic periodic paralysis.

Jurkat-Rott and Lehmann-Horn (2007) again refuted the pathogenicity of the R83H variant, noting that it had been identified in 1.17% of patients and 1.16% of healthy controls, which does not support disease causality.


.0002 BRUGADA SYNDROME 6 (1 family)

KCNE3, ARG99HIS
  
RCV000005880...

Brugada Syndrome

In 4 affected members of a Danish family with Brugada syndrome (613119), Delpon et al. (2008) identified heterozygosity for a G-to-A transition in the KCNE3 gene, predicted to result in an arg99-to-his (R99H) substitution. The mutation was not found in 3 unaffected family members, in 200 Danish control alleles, or in an additional 206 alleles of Caucasian European controls. In whole-cell patch-clamp studies, cotransfection of R99H-mutant KCNE3 with KCND3 (605411) resulted in a significant increase in transient outward current intensity compared to wildtype; the gain of function demonstrated a positive dominant effect, since the increase in current was comparable with or without the presence of wildtype KCNE3. Using tissues isolated from the left atrial appendages of human hearts, coimmunoprecipitation of Kv4.3 and KCNE3 was demonstrated.

Acquired Long QT Syndrome, Susceptibility to (1 patient)

In a 76-year-old Japanese woman with repeated episodes of paroxysmal atrial fibrillation (see 608583), who developed torsade de pointes with a prolonged QT interval (see 192500) after taking the drug disopyramide but was negative for mutation in 5 known LQT genes, Ohno et al. (2009) identified heterozygosity for the R99H mutation in KCNE3. There was no family history of sudden cardiac death or LQT, and family members declined to participate in the study. The mutation was not found in 200 healthy Japanese individuals from the general population. Electrophysiologic analysis demonstrated that the R99H mutant significantly reduced outward current compared to wildtype.


.0003 VARIANT OF UNKNOWN SIGNIFICANCE

KCNE3, THR4ALA
  
RCV000114366...

The variant is classified as a variant of unknown significance because its contribution to a cardiac phenotype has not been confirmed.

In a 16-year-old Japanese boy with prolonged QT interval (see 192500) discovered on a routine annual health examination, who had no history of faintness or syncope, Ohno et al. (2009) identified heterozygosity for a c.10A-G transition in the KCNE3 gene, resulting in a thr4-to-ala (T4A) substitution. The patient's resting ECG showed bradycardia for age (48 bpm) and QT prolongation (QTc = 525 ms). He was also found to carry a variant in the KCNH2 gene (G572S) known to be associated with LQT2 (see 613688). There was no family history of syncope or sudden death. His asymptomatic mother and sister, who both exhibited prolongation of QTc on ECG (520 ms and 560 ms), were also heterozygous for the same 2 variants. Ohno et al. (2009) also detected the T4A KCNE3 variant in a 68-year-old Japanese woman who experienced hypokalemia-induced torsade de pointes at age 60 years. Her asymptomatic daughter, who had borderline QTc prolongation on ECG, also carried the T4A variant. Electrophysiologic analysis showed that the T4A KCNE3 variant did not have a statistically significant effect on current density or deactivation kinetics. The KCNE3 T4A variant was not found in 200 healthy Japanese individuals from the general population.

In a 55-year-old Japanese man with syncope and a Brugada-like pattern on his electrocardiogram (see 613119), Nakajima et al. (2012) identified heterozygosity for the T4A mutation in the KCNE3 gene. Beginning in his fourth decade of life, the patient had several episodes of syncope under specific conditions, such as standing up after drinking alcohol. There was no family history of sudden cardiac death. ECG showed saddle-type ST segment elevation in the right precordial leads, with a QTc of 414 ms. After provocation with pilsicainide, a coved-type ST segment elevation appeared in the right precordial leads at the second intercostal space. Upon electrophysiologic assessment, nonsustained polymorphic ventricular tachycardia was induced, but not ventricular fibrillation. Head-up tilt test provoked hypotension and bradycardia, followed by syncope, and the patient was diagnosed as having neurally mediated (vasovagal) syncope (see 609289). Functional analysis in CHO cells showed significantly increased peak current densities with the mutant compared to wildtype channels, but there was no effect on time to peak or inactivation kinetics.


REFERENCES

  1. Abbott, G. W., Butler, M. H., Bendahhou, S., Dalakas, M. C., Ptacek, L. J., Goldstein, S. A. N. MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 104: 217-231, 2001. [PubMed: 11207363, related citations] [Full Text]

  2. Abbott, G. W., Butler, M. H., Goldstein, S. A. N. Phosphorylation and protonation of neighboring MiRP2 sites: function and pathophysiology of MiRP2-Kv3.4 potassium channels in periodic paralysis. FASEB J. 20: 293-301, 2006. [PubMed: 16449802, related citations] [Full Text]

  3. Abbott, G. W., Sesti, F., Splawski, I., Buck, M. E., Lehmann, M. H., Timothy, K. W., Keating, M. T., Goldstein, S. A. N. MiRP1 forms I(Kr) potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97: 175-187, 1999. [PubMed: 10219239, related citations] [Full Text]

  4. Delpon, E., Cordeiro, J. M., Nunez, L., Thomsen, P. E. B., Guerchicoff, A., Pollevick, G. D., Wu, Y., Kanters, J. K., Larsen, C. T., Hofman-Bang, J., Burashnikov, E., Christiansen, M., Antzelevitch, C. Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circ. Arrhythm. Electrophysiol. 1: 209-218, 2008. Note: Erratum: Circ. Arrhythm. Electrophysiol. 1: e2, 2008. [PubMed: 19122847, related citations] [Full Text]

  5. Dias Da Silva, M. R., Cerutti, J. M., Arnaldi, L. A. T., Maciel, R. M. B. A mutation in the KCNE3 potassium channel gene is associated with susceptibility to thyrotoxic hypokalemic periodic paralysis. J. Clin. Endocr. Metab. 87: 4881-4884, 2002. [PubMed: 12414843, related citations] [Full Text]

  6. Jurkat-Rott, K., Lehmann-Horn, F. Periodic paralysis mutation MiRP2-R83H in controls: interpretations and general recommendation. Neurology 62: 1012-1015, 2004. [PubMed: 15037716, related citations] [Full Text]

  7. Jurkat-Rott, K., Lehmann-Horn, F. Genotype-phenotype correlation and therapeutic rationale in hyperkalemic periodic paralysis. Neurotherapeutics 4: 216-224, 2007. [PubMed: 17395131, related citations] [Full Text]

  8. Melman, Y. F., Um, S. Y., Krumerman, A., Kagan, A., McDonald, T. V. KCNE1 binds to the KCNQ1 pore to regulate potassium channel activity. Neuron 42: 927-937, 2004. [PubMed: 15207237, related citations] [Full Text]

  9. Nakajima, T., Wu, J., Kaneko, Y., Ashihara, T., Ohno, S., Irie, T., Ding, W.-G., Matsuura, H., Kurabayashi, M., Horie, M. KCNE3 T4A as the genetic basis of Brugada-pattern electrocardiogram. Circ. J. 76: 2763-2772, 2012. [PubMed: 22987075, related citations] [Full Text]

  10. Ohno, S., Toyoda, F., Zankov, D. P., Yoshida, H., Makiyama, T., Tsuji, K., Honda, T., Obayashi, K., Ueyama, H., Shimizu, W., Miyamoto, Y., Kamakura, S., Matsuura, H., Kita, T., Horie, M. Novel KCNE3 mutation reduces repolarizing potassium current and associated with long QT syndrome. Hum. Mutat. 30: 557-563, 2009. [PubMed: 19306396, related citations] [Full Text]

  11. Schroeder, B. C., Waldegger, S., Fehr, S., Bleich, M., Warth, R., Greger, R., Jentsch, T. J. A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature 403: 196-199, 2000. [PubMed: 10646604, related citations] [Full Text]

  12. Sternberg, D., Tabti, N., Fournier, E., Hainque, B., Fontaine, B. Lack of association of the potassium channel-associated peptide MiRP2-R83H variant with periodic paralysis. Neurology 61: 857-859, 2003. [PubMed: 14504341, related citations] [Full Text]

  13. Tang, N. L. S., Chow, C. C., Ko, G. T. C., Tai, M. H. L., Kwok, R., Yao, X. Q., Cockram, C. S. No mutation in the KCNE3 potassium channel gene in Chinese thyrotoxic hypokalaemic periodic paralysis patients. Clin. Endocr. 61: 109-112, 2004. [PubMed: 15212652, related citations] [Full Text]


Marla J. F. O'Neill - updated : 3/28/2014
Cassandra L. Kniffin - updated : 11/24/2009
Marla J. F. O'Neill - updated : 11/11/2009
Patricia A. Hartz - updated : 5/16/2005
Cassandra L. Kniffin - updated : 8/31/2004
John A. Phillips, III - updated : 4/8/2003
Stylianos E. Antonarakis - updated : 1/29/2001
Creation Date:
Ada Hamosh : 1/14/2000
carol : 09/19/2018
carol : 03/29/2018
carol : 03/28/2018
joanna : 06/24/2016
carol : 4/2/2014
mcolton : 3/28/2014
carol : 12/15/2011
carol : 2/5/2010
ckniffin : 2/1/2010
ckniffin : 11/24/2009
wwang : 11/11/2009
terry : 11/11/2009
wwang : 5/20/2005
wwang : 5/16/2005
carol : 9/3/2004
ckniffin : 8/31/2004
tkritzer : 4/16/2003
carol : 4/15/2003
tkritzer : 4/15/2003
terry : 4/8/2003
ckniffin : 2/5/2003
mgross : 1/30/2001
mgross : 1/29/2001
mgross : 1/29/2001
alopez : 1/14/2000

* 604433

POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 3; KCNE3


Alternative titles; symbols

MINIMUM POTASSIUM ION CHANNEL-RELATED PEPTIDE 2; MIRP2
MINK-RELATED PEPTIDE 2


HGNC Approved Gene Symbol: KCNE3

Cytogenetic location: 11q13.4     Genomic coordinates (GRCh38): 11:74,454,841-74,467,549 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
11q13.4 ?Brugada syndrome 6 613119 3

TEXT

Cloning and Expression

Abbott et al. (1999) cloned the potassium channel beta subunit KCNE3 by homology to KCNE1 (176261). KCNE3 is a 103-amino acid protein with a relative molecular mass of about 12 kD that displays roughly 35% identity to other KCNE proteins within the single transmembrane domain and a following short stretch. Northern blot analysis revealed a prominent band in the kidney, moderate expression in the small intestine, and weaker bands in most other tissues, including colon and heart. By Northern blot analysis, Abbott et al. (2001) detected KCNE3 mRNA in skeletal muscle, but not in small intestine, colon, kidney, or liver.


Mapping

By radiation hybrid analysis, Abbott et al. (2001) mapped the KCNE3 gene to chromosome 11q13-q14.


Gene Function

When KCNQ1 (607542) interacts with the beta subunit KCNE1, a slow depolarization-activated potassium current I(Ks) is formed that is affected in some forms of cardiac arrhythmia. Schroeder et al. (2000) demonstrated that the beta subunit KCNE3 markedly changes KCNQ1 properties to yield currents that are nearly instantaneous and depend linearly on voltage. KCNE3 also suppresses the currents of KCNQ4 (603537) and HERG (see 152427) potassium channels. In the intestine, KCNQ1 and KCNE3 mRNAs colocalized in crypt cells. This localization, and the pharmacology, voltage dependence, and stimulation by cyclic AMP of KCNQ1/KCNE3 currents, indicated that these proteins may assemble to form the potassium channel that is important for cyclic AMP-stimulated intestinal chloride secretion and that is involved in secretory diarrhea and cystic fibrosis.

In skeletal muscle cells, Abbott et al. (2001) demonstrated that KCNE3 forms stable complexes with the pore-forming unit Kv3.4 (KCNC4; 176265), resulting in potassium channels with increased conductance, faster recovery from inactivation, and slower cumulative inactivation. KCNE3-KCNE4 channels are 80-fold more active at -40 mv and establish the resting membrane potential of skeletal muscle cells. Western blot analysis detected the KCNE3 protein in skeletal muscle plasma membranes.

Melman et al. (2004) showed that KCNE1 and KCNE3 associate with an extended binding interface of KCNQ1 that includes structures within the channel pore and C terminus.


Molecular Genetics

Brugada Syndrome 6

Delpon et al. (2008) sequentially screened 14 ion channel genes in 105 probands with Brugada syndrome (see 601144) and identified a heterozygous mutation in the KCNE3 gene (R99H; 604433.0002) in a proband from a Danish pedigree (Brugada syndrome-6; BRGDA6, 613119). Cotransfection of R99H-mutant KCNE3 with KCNQ1 (607542) produced no alteration in tail current magnitude or kinetics, whereas cotransfection of R99H-mutant KCNE3 with KCND3 (605411) resulted in a significant increase in the transient outward current intensity compared to wildtype. The authors also demonstrated coimmunoprecipitation of Kv4.3 and KCNE3 in human left atrial appendage tissue.

In 40 consecutive Japanese patients with a Brugada-like pattern on electrocardiography, Nakajima et al. (2012) analyzed all coding exons of the SCN5A (600163), SCN1B (600235), SCN3B (608214), KCNE5 (300328), and KCNE3 genes, and identified a 55-year-old man who was heterozygous for a T4A mutation in KCNE3 (604433.0003) and negative for mutation in the other 4 genes as well as in the CACNA1C (114205) and CACNB2 (600003) genes. Functional analysis demonstrated a significantly increased current density with the T4A mutant compared to wildtype.

Possible Role in Periodic Paralysis

Although Abbott et al. (2001) identified an arg83-to-his (R83H; 604433.0001) substitution in 2 of 100 patients with hyperkalemic periodic paralysis (HYPP; 170500) and hypokalemic periodic paralysis (HOKPP; 170400), respectively, Sternberg et al. (2003) and Jurkat-Rott and Lehmann-Horn (2004) concluded that the R83H variant does not play a causative role in periodic paralysis. See 604433.0001 for detailed discussion.

Dias Da Silva et al. (2002) identified the R83H variant in a sporadic case of thyrotoxic periodic paralysis (TPP; 188580). The patient was a 44-year-old Caucasian man of Portuguese descent who had experienced episodic paralysis for 2 years before developing signs of thyrotoxicosis caused by Graves disease (275000). Tang et al. (2004) did not identify the R83H substitution, or any mutations in the KCNE3 gene, among 79 Chinese patients with thyrotoxic hypokalemic periodic paralysis.

Possible Role in Acquired Long QT Syndrome

In 485 Japanese probands with congenital or acquired long QT syndrome (see LQT1, 192500), who on electrocardiography exhibited QT interval prolongation of 460 ms or more or who had documented torsade de pointes, Ohno et al. (2009) analyzed 5 known LQT genes (KCNQ1, 607542; KCNH2, 152427; SCN5A, 600163; KCNE1, 176261; and KCNE2, 603796) as well as the candidate gene KCNE3. A 76-year-old woman with acquired LQT who was negative for mutation in the 5 known LQT genes was found to be heterozygous for the R99H missense mutation in KCNE3 (604433.0002), previously associated with Brugada syndrome. In another 2 unrelated probands with LQT, Ohno et al. (2009) identified a different missense mutation in KCNE3 (T4A; 604433.0003); however, in 1 family, the proband and his asymptomatic mother and sister were also heterozygous for a known LQT-associated variant in the KCNH2 gene (G572S), and electrophysiologic analysis showed that the KCNE3 T4A variant did not have a statistically significant effect on current density.


ALLELIC VARIANTS 3 Selected Examples):

.0001   RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

KCNE3, ARG83HIS
SNP: rs17215437, gnomAD: rs17215437, ClinVar: RCV000005879, RCV000171813, RCV000223897, RCV000253742, RCV000415218, RCV000538199, RCV000852657, RCV000988595

This variant, formerly titled HYPOKALEMIC PERIODIC PARALYSIS, HYPERKALEMIC PERIODIC PARALYSIS, and SUSCEPTIBILITY TO THYROTOXIC PERIODIC PARALYSIS based on the findings of Abbott et al. (2001) and Dias Da Silva et al. (2002), has been reclassified based on the findings of Sternberg et al. (2003) and Jurkat-Rott and Lehmann-Horn (2004).

Abbott et al. (2001) identified a 340G-A transition in the KCNE3 gene, resulting in an arg83-to-his (R83H) substitution in 2 of 100 patients with atypical forms of hyperkalemic periodic paralysis (HYPP; 170500) and hypokalemic periodic paralysis (HOKPP; 170400), respectively. However, Sternberg et al. (2003) and Jurkat-Rott and Lehmann-Horn (2004) concluded that the R83H variant does not play a causative role in periodic paralysis and that it is a polymorphism.

Abbott et al. (2001) reported a male proband with atypical HYPP who was negative for mutations in the SCN4A gene and who carried the R83H variant. He presented at 22 months of age with episodic weakness of the extremities. Most episodes came on during sleep and were brief (12 hours), although they occasionally lasted for days. Serum potassium levels during attacks were normal. High carbohydrate meals helped resolve attacks, and treatment with a carbonic anhydrase inhibitor prevented attacks. The age at onset, frequent nature of attacks, and improvement with carbohydrate loading were all consistent with HYPP; however, provocative testing with potassium had not been performed. Frequent attacks upon awakening and absence of myotonia were considered atypical for this diagnosis. Abbott et al. (2001) reported a male proband with atypical HOKPP who was negative for mutations in the SCN4A and CACNA1S genes and who carried the R83H variant. He had onset of episodic paralytic weakness at the age of 14 years. Episodes were characterized by weakness primarily affecting the lower extremities and lasting hours to days, and were usually precipitated by strenuous exercise followed by rest or after prolonged sitting. Carbohydrate ingestion did not precipitate attacks, alcohol intake appeared to facilitate recovery from an attack, and potassium had no effect. He was classified as having hypokalemic periodic paralysis because of the typical age of onset, paralytic attacks that most often occurred after exercise, a low potassium level during a spontaneous attack, and the ability to precipitate an attack with insulin and glucose on 1 occasion. Atypical for this diagnosis was that a second provocative test was negative and that attacks usually occurred while awake. The variant was not found in DNA from a control population of 120 unaffected individuals, suggesting to them that it does not represent a polymorphism.

Abbott et al. (2001) reported functional expression studies that showed that the mutant R83H KCNE3-Kv3.4 complexes exhibited reduced current density and diminished capacity to set resting membrane potential as a dominant-negative effect compared to wildtype. In in vitro studies, Abbott et al. (2006) found that the R83H variant shifts the voltage-dependence of channel activation in response to pH change. The current through the mutant channel decreased compared to wildtype as intracellular pH was lowered. The authors suggested that R83H acts as a regulatory domain, and concluded that the variation may predispose to the development of periodic paralysis.

In contrast, Sternberg et al. (2003) did not identify the R83H mutation in 64 probands with either HYPP or HOKPP in whom mutations in the SCN4A and CACNA1S genes had been excluded. One patient with HOKPP had the R83H change, but he also had a mutation in the SCN4A gene (R672H; 603967.0016). His father, who had the same clinical phenotype and the SCN4A mutation, did not carry the R83H mutation, whereas the asymptomatic mother carried the R83H variant. The findings yielded a frequency of 0.0096 in patients with periodic paralysis (1 in 104) and 0.0158 (8 of 506) in healthy controls. Likewise, Jurkat-Rott and Lehmann-Horn (2004) identified the R83H mutation in 1 of 76 patients with HYPP, in 1 of 61 patients with paramyotonia congenita (608390), in 5 unaffected relatives, in 0 of 8 patients with TTPP, and in 3 of 321 healthy controls, suggesting that it is a polymorphism. Provocation of an unaffected carrier with glucose or potassium administration did not induce weakness. The authors offered a formula for determining causality of a mutation based on reduced penetrance, but concluded that the R83H mutation does not cause these muscle disorders.

Dias Da Silva et al. (2002) identified the R83H substitution in 1 of 15 patients with thyrotoxic hypokalemic periodic paralysis (188580). The patient was a 44-year-old Caucasian man of Portuguese descent who experienced episodic paralysis for 2 years before developing thyrotoxicosis caused by Graves disease (275000). Two of his 3 offspring, all asymptomatic, were found to have the same variant. Tang et al. (2004) did not identify the R83H substitution, or any mutations in the KCNE3 gene, among 79 Chinese patients with thyrotoxic hypokalemic periodic paralysis.

Jurkat-Rott and Lehmann-Horn (2007) again refuted the pathogenicity of the R83H variant, noting that it had been identified in 1.17% of patients and 1.16% of healthy controls, which does not support disease causality.


.0002   BRUGADA SYNDROME 6 (1 family)

KCNE3, ARG99HIS
SNP: rs121908441, gnomAD: rs121908441, ClinVar: RCV000005880, RCV000170965, RCV000171754, RCV000618438

Brugada Syndrome

In 4 affected members of a Danish family with Brugada syndrome (613119), Delpon et al. (2008) identified heterozygosity for a G-to-A transition in the KCNE3 gene, predicted to result in an arg99-to-his (R99H) substitution. The mutation was not found in 3 unaffected family members, in 200 Danish control alleles, or in an additional 206 alleles of Caucasian European controls. In whole-cell patch-clamp studies, cotransfection of R99H-mutant KCNE3 with KCND3 (605411) resulted in a significant increase in transient outward current intensity compared to wildtype; the gain of function demonstrated a positive dominant effect, since the increase in current was comparable with or without the presence of wildtype KCNE3. Using tissues isolated from the left atrial appendages of human hearts, coimmunoprecipitation of Kv4.3 and KCNE3 was demonstrated.

Acquired Long QT Syndrome, Susceptibility to (1 patient)

In a 76-year-old Japanese woman with repeated episodes of paroxysmal atrial fibrillation (see 608583), who developed torsade de pointes with a prolonged QT interval (see 192500) after taking the drug disopyramide but was negative for mutation in 5 known LQT genes, Ohno et al. (2009) identified heterozygosity for the R99H mutation in KCNE3. There was no family history of sudden cardiac death or LQT, and family members declined to participate in the study. The mutation was not found in 200 healthy Japanese individuals from the general population. Electrophysiologic analysis demonstrated that the R99H mutant significantly reduced outward current compared to wildtype.


.0003   VARIANT OF UNKNOWN SIGNIFICANCE

KCNE3, THR4ALA
SNP: rs200856070, gnomAD: rs200856070, ClinVar: RCV000114366, RCV000455941, RCV000490275, RCV000621765, RCV000988596

The variant is classified as a variant of unknown significance because its contribution to a cardiac phenotype has not been confirmed.

In a 16-year-old Japanese boy with prolonged QT interval (see 192500) discovered on a routine annual health examination, who had no history of faintness or syncope, Ohno et al. (2009) identified heterozygosity for a c.10A-G transition in the KCNE3 gene, resulting in a thr4-to-ala (T4A) substitution. The patient's resting ECG showed bradycardia for age (48 bpm) and QT prolongation (QTc = 525 ms). He was also found to carry a variant in the KCNH2 gene (G572S) known to be associated with LQT2 (see 613688). There was no family history of syncope or sudden death. His asymptomatic mother and sister, who both exhibited prolongation of QTc on ECG (520 ms and 560 ms), were also heterozygous for the same 2 variants. Ohno et al. (2009) also detected the T4A KCNE3 variant in a 68-year-old Japanese woman who experienced hypokalemia-induced torsade de pointes at age 60 years. Her asymptomatic daughter, who had borderline QTc prolongation on ECG, also carried the T4A variant. Electrophysiologic analysis showed that the T4A KCNE3 variant did not have a statistically significant effect on current density or deactivation kinetics. The KCNE3 T4A variant was not found in 200 healthy Japanese individuals from the general population.

In a 55-year-old Japanese man with syncope and a Brugada-like pattern on his electrocardiogram (see 613119), Nakajima et al. (2012) identified heterozygosity for the T4A mutation in the KCNE3 gene. Beginning in his fourth decade of life, the patient had several episodes of syncope under specific conditions, such as standing up after drinking alcohol. There was no family history of sudden cardiac death. ECG showed saddle-type ST segment elevation in the right precordial leads, with a QTc of 414 ms. After provocation with pilsicainide, a coved-type ST segment elevation appeared in the right precordial leads at the second intercostal space. Upon electrophysiologic assessment, nonsustained polymorphic ventricular tachycardia was induced, but not ventricular fibrillation. Head-up tilt test provoked hypotension and bradycardia, followed by syncope, and the patient was diagnosed as having neurally mediated (vasovagal) syncope (see 609289). Functional analysis in CHO cells showed significantly increased peak current densities with the mutant compared to wildtype channels, but there was no effect on time to peak or inactivation kinetics.


REFERENCES

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Contributors:
Marla J. F. O'Neill - updated : 3/28/2014
Cassandra L. Kniffin - updated : 11/24/2009
Marla J. F. O'Neill - updated : 11/11/2009
Patricia A. Hartz - updated : 5/16/2005
Cassandra L. Kniffin - updated : 8/31/2004
John A. Phillips, III - updated : 4/8/2003
Stylianos E. Antonarakis - updated : 1/29/2001

Creation Date:
Ada Hamosh : 1/14/2000

Edit History:
carol : 09/19/2018
carol : 03/29/2018
carol : 03/28/2018
joanna : 06/24/2016
carol : 4/2/2014
mcolton : 3/28/2014
carol : 12/15/2011
carol : 2/5/2010
ckniffin : 2/1/2010
ckniffin : 11/24/2009
wwang : 11/11/2009
terry : 11/11/2009
wwang : 5/20/2005
wwang : 5/16/2005
carol : 9/3/2004
ckniffin : 8/31/2004
tkritzer : 4/16/2003
carol : 4/15/2003
tkritzer : 4/15/2003
terry : 4/8/2003
ckniffin : 2/5/2003
mgross : 1/30/2001
mgross : 1/29/2001
mgross : 1/29/2001
alopez : 1/14/2000