Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice.

The KvLQT1 gene encodes a voltage-gated potassium channel. Mutations in KvLQT1 underlie the dominantly transmitted Ward-Romano long QT syndrome, which causes cardiac arrhythmia, and the recessively transmitted Jervell and Lange-Nielsen syndrome, which causes both cardiac arrhythmia and congenital deafness. KvLQT1 is also disrupted by balanced germline chromosomal rearrangements in patients with Beckwith-Wiedemann syndrome (BWS), which causes prenatal overgrowth and cancer. Because of the diverse human disorders and organ systems affected by this gene, we developed an animal model by inactivating the murine Kvlqt1. No electrocardiographic abnormalities were observed. However, homozygous mice exhibited complete deafness, as well as circular movement and repetitive falling, suggesting imbalance. Histochemical study revealed severe anatomic disruption of the cochlear and vestibular end organs, suggesting that Kvlqt1 is essential for normal development of the inner ear. Surprisingly, homozygous mice also displayed threefold enlargement by weight of the stomach resulting from mucous neck cell hyperplasia. Finally, there were no features of BWS, suggesting that Kvlqt1 is not responsible for BWS.

[1]  S. Waldegger,et al.  A constitutively open potassium channel formed by KCNQ1 and KCNE3 , 2000, Nature.

[2]  P. Gleeson,et al.  Gastric H(+),K(+)-adenosine triphosphatase beta subunit is required for normal function, development, and membrane structure of mouse parietal cells. , 1999, Gastroenterology.

[3]  A. Feinberg,et al.  Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[4]  D. Roden,et al.  Replacement by homologous recombination of the minK gene with lacZ reveals restriction of minK expression to the mouse cardiac conduction system. , 1999, Circulation research.

[5]  A. Feinberg,et al.  Strain-dependent developmental relaxation of imprinting of an endogenous mouse gene, Kvlqt1. , 1998, Genomics.

[6]  D. Escande,et al.  Adult KCNE1-knockout mice exhibit a mild cardiac cellular phenotype. , 1998, Biochemical and biophysical research communications.

[7]  A. Feinberg,et al.  Somatic mutation of TSSC5, a novel imprinted gene from human chromosome 11p15.5. , 1998, Cancer research.

[8]  M. Ladanyi,et al.  Olfactory neuroblastoma is not related to the Ewing family of tumors: absence of EWS/FLI1 gene fusion and MIC2 expression. , 1998, The American journal of surgical pathology.

[9]  G. Boivin,et al.  Targeted disruption of the murine Na+/H+ exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. , 1998, The Journal of clinical investigation.

[10]  K. Pfeifer,et al.  Imprinting of mouse Kvlqt1 is developmentally regulated. , 1998, Human molecular genetics.

[11]  M. Ladanyi,et al.  Erratum: Detection of the SYT-SSX chimeric RNA of synovial sarcoma in paraffin-embedded tissue and its application in problematic cases (Modern Pathology (1998) 11 (65-71)) , 1998 .

[12]  M. Ladanyi,et al.  Detection of the SYT-SSX chimeric RNA of synovial sarcoma in paraffin-embedded tissue and its application in problematic cases. , 1998, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[13]  G. Breithardt,et al.  KCNE1 mutations cause Jervell and Lange-Nielsen syndrome , 1997, Nature Genetics.

[14]  M. Sanguinetti,et al.  Mutations in the hminK gene cause long QT syndrome and suppress lKs function , 1997, Nature Genetics.

[15]  H. Calkins,et al.  Beat-to-beat QT interval variability: novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy. , 1997, Circulation.

[16]  D. Ryugo,et al.  Projections from the ventral cochlear nucleus to the dorsal cochlear nucleus in rats , 1997, The Journal of comparative neurology.

[17]  A. Feinberg,et al.  Low frequency of p57KIP2 mutation in Beckwith-Wiedemann syndrome. , 1997, American journal of human genetics.

[18]  Glenn I. Fishman,et al.  A minK–HERG complex regulates the cardiac potassium current IKr , 1997, Nature.

[19]  P. Coumel,et al.  A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome , 1997, Nature Genetics.

[20]  A. Wilde,et al.  KVLQT1, the rhythm of imprinting , 1997, Nature Genetics.

[21]  A. Feinberg,et al.  Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements , 1997, Nature Genetics.

[22]  S. Heinemann,et al.  Inner Ear Defects Induced by Null Mutationof the isk Gene , 1996, Neuron.

[23]  P. J. Wang,et al.  In vivo cardiac electrophysiology studies in the mouse. , 1996, Circulation.

[24]  Y. Fukushima,et al.  An imprinted gene p57KIP2 is mutated in Beckwith–Wiedemann syndrome , 1996, Nature Genetics.

[25]  H. Duff,et al.  Developmental changes in the delayed rectifier K+ channels in mouse heart. , 1996, Circulation research.

[26]  H J Duff,et al.  Identification and characteristics of delayed rectifier K+ current in fetal mouse ventricular myocytes. , 1996, The American journal of physiology.

[27]  R. Coffey,et al.  Overexpression of transforming growth factor-alpha alters differentiation of gastric cell lineages. , 1996, Digestive diseases and sciences.

[28]  P. Doevendans,et al.  Developmental changes in ionic channel activity in the embryonic murine heart. , 1996, Circulation research.

[29]  T. Wang,et al.  Hypertrophic gastropathy in Helicobacter felis-infected wild-type C57BL/6 mice and p53 hemizygous transgenic mice. , 1996, Gastroenterology.

[30]  G. Landes,et al.  Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias , 1996, Nature Genetics.

[31]  D. Roden,et al.  Anti-minK antisense decreases the amplitude of the rapidly activating cardiac delayed rectifier K+ current. , 1995, Circulation Research.

[32]  A. Varró,et al.  Pathways of processing of the gastrin precursor in rat antral mucosa. , 1995, The Journal of clinical investigation.

[33]  E. Marbán,et al.  Electrophysiological properties of neonatal mouse cardiac myocytes in primary culture. , 1994, The Journal of physiology.

[34]  J. Nadol,et al.  Otopathology in a case of multichannel cochlear implantation , 1994, The Laryngoscope.

[35]  A. Feinberg,et al.  Loss of imprinting in human cancer. , 1994, Cold Spring Harbor symposia on quantitative biology.

[36]  C. P. Leblond,et al.  Dynamics of epithelial cells in the corpus of the mouse stomach. III. Inward migration of neck cells followed by progressive transformation into zymogenic cells , 1993, The Anatomical record.

[37]  R. Cohen,et al.  An Efficient Algorithm for Spectral Analysis of Heart Rate Variability , 1986, IEEE Transactions on Biomedical Engineering.