Correspondence
Molecular Basis of the Long-QT Syndrome
N Engl J Med 1997; 337:1011-1013October 2, 1997
- Article
To the Editor:
Splawski et al. (May 29 issue)1 and others2 have shown at the molecular level that the Jervell and Lange–Nielsen syndrome (prolonged QT interval on the electrocardiogram, associated with profound congenital deafness) may be caused by a homozygous mutation in the KVLQT1 gene, confirming that the Jervell and Lange–Nielsen syndrome and the Romano–Ward syndrome are allelic. Genetic heterogeneity has previously been demonstrated in the Romano–Ward syndrome, in that a heterozygous mutation in any of three genes, KVLQT1 (at the LQT1 locus), HERG (at the LQT2 locus), and SCN5A (at the LQT3 locus), and another as yet unidentified gene (at the LQT4 locus) can cause isolated long-QT syndrome.3
Genetic heterogeneity has now been suggested in the Jervell and Lange–Nielsen syndrome1,2 because of the results of linkage analysis in a sibship that was described previously.4 The affected siblings in this family were found to have inherited different paternal alleles for a marker closely linked to the LQT1 locus (Harvey–ras). The Harvey–ras marker had not previously shown any recombinations with the disease locus in families with the Romano–Ward syndrome.
Refined mapping of the LQT1 locus, placing it distal to the marker D11S1318,2,5 together with the availability of polymorphic markers closer to the KVLQT1 gene, prompted reanalysis of this family. Haplotyping showed that recombination has occurred distal to the Harvey–ras marker on the paternal chromosome and that both boys have inherited the same parental alleles flanking the disease gene (Figure 1AFigure 1
Results of Haplotyping for Three Markers, D11S922, D11S1318, and D11S4146, on Chromosome 11 around the LQT1 Locus in Two British Families.). Therefore, the data in this family are now consistent with mutation at the LQT1 locus and should no longer be cited as evidence of the existence of genetic heterogeneity in the Jervell and Lange–Nielsen syndrome.Haplotyping of another British family, however, does provide strong evidence of genetic heterogeneity in the Jervell and Lange–Nielsen syndrome. The parents of the affected boys are consanguineous (first cousins once removed). In the context of a rare recessive disorder, the boys should be homozygous for a single mutation inherited from a common ancestor and homozygous for genetic markers around the mutant gene.5 Haplotyping shows that although the boys have inherited the same parental alleles, they are not homozygous at any of the surrounding marker loci (Figure 1B). Furthermore, haplotyping for markers around LQT2, LQT3, and LQT4 shows no evidence of homozygosity in these regions, which suggests that mutation of a different gene must cause the Jervell and Lange–Nielsen syndrome in this family.
5 ReferencesMaria Bitner-Glindzicz, M.R.C.P., Ph.D.
Jessica Tyson, B.Sc.
Institute of Child Health, London WC1N 1EH, United KingdomRuth Jamieson, Ph.D.
St. George's Hospital Medical School, London SW17 0RE, United Kingdom1
Splawski I ,Timothy KW ,Vincent GM ,Atkinson DL ,Keating MT . Molecular basis of the long-QT syndrome associated with deafness. N Engl J Med 1997;336:1562-1567
Full Text | Web of Science | Medline2
Neyroud N ,Tesson F ,Denjoy I , et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet 1997;15:186-189
CrossRef | Web of Science | Medline3
Third and long (QT)Nat Genet 1996;12:1-2
CrossRef | Web of Science | Medline4
Jeffery S ,Jamieson R ,Patton MA ,Till J . Long QT and Harvey-ras. Lancet 1992;339:255-255
CrossRef | Web of Science | Medline5
Dausse E ,Denjoy I ,Kahlem P , et al. Readjusting the localization of long QT syndrome gene on chromosome 11p15. C R Acad Sci III 1995;318:879-885
Web of Science | Medline
Author/Editor Response
Dr. Keating replies:
To the Editor: In our article, we proposed that mutations in the minK (IsK ) gene might also be responsible for the Jervell and Lange–Nielsen syndrome.1 This hypothesis was based on data showing that minK joins with KVLQT protein to form cardiac IKs channels2,3 and that KVLQT1 mutations cause this disorder.1,4 The data presented by Bitner-Glindzicz et al. support, but do not prove, the hypothesis that mutations in a second gene can cause the Jervell and Lange–Nielsen syndrome. Mutational analysis of DNA from this and other consanguineous families may prove that homozygous mutations of the minK gene also cause the Jervell and Lange–Nielsen syndrome.
4 ReferencesMark T. Keating, M.D.
Howard Hughes Medical Institute, Salt Lake City, UT 841121
Splawski I ,Timothy KW ,Vincent GM ,Atkinson DL ,Keating MT . Molecular basis of the long-QT syndrome associated with deafness. N Engl J Med 1997;336:1562-1567
Full Text | Web of Science | Medline2
Sanguinetti MC ,Curran ME ,Zou A , et al. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 1996;384:80-83
CrossRef | Web of Science | Medline3
Barhanin J ,Lesage F ,Guillemare E ,Fink M ,Lazdunski M ,Romey G . K(V)LQT1 and IsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 1996;384:78-80
CrossRef | Web of Science | Medline4
Neyroud N ,Tesson F ,Denjoy I , et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet 1997;15:186-189
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Lisbeth Tranebjærg. 2003. Jervell and Lange-Nielsen Syndrome. .
CrossRef2
Y Hong, Pm Rautaharju, Pn Hopkins, Dk Arnett, L Djoussé, Js Pankow, P Sholinsky, Dc Rao, Ma Province. (2001) Familial aggregation of QT-interval variability in a general population: results from the NHLBI Family Heart Study. Clinical Genetics 59:3, 171-177
CrossRef3
Lisbeth Tranebj
rg, J
CrossRef
