Pathology of the Ear in the Cardio-Auditory Syndrome of Jervell and Lange-Nielsen (Recessive Deafness with Electrocardiographic Abnormalities)

Friedmann, I.; Fraser, G. R.; Froggatt, P.

doi:10.1017/s002221510006552x

Cited by 104 publications

(40 citation statements)

References 16 publications

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“…Both IsK knockout mice and JLN patients appear to have similar developmental defects involving the strial marginal cells of the cochlea capsule, resulting in deficient endolymph production and congenital deafness. 16,17 These findings support the idea that mutations in IsK may be responsible for JLN syndrome. To test this hypothesis, 84 Romano-Ward and 4 JLN patients were examined for possible mutations of KCNE1.…”

supporting

confidence: 66%

Mutation of the Gene for I sK Associated With Both Jervell and Lange-Nielsen and Romano-Ward Forms of Long-QT Syndrome

Duggal¹,

Vesely²,

et al. 1998

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Background-Long-QT syndrome (LQTS) is a disorder of ventricular repolarization characterized by a prolonged QT interval, syncope, seizures, and sudden death. Recently, three forms of LQTS have been shown to result from mutations in potassium or sodium ion channel genes: KVLQT1 for LQT1, HERG for LQT2, and SCN5A for LQT3. IsK, an apparent potassium channel subunit encoded by KCNE1 on chromosome 21, regulates both KVLQT1 and HERG. This relationship makes KCNE1 a likely candidate gene, because mutations of these genes are known to cause both the autosomal dominant Romano-Ward and recessive Jervell and Lange-Nielsen (JLN) forms of LQTS. Methods and Results-We screened 84 unrelated patients with Romano-Ward and 4 with JLN for possible mutations in KCNE1. We identified one homozygous mutation in a JLN patient that results in the nonconservative substitution of Asn for Asp at amino acid 76. The patient is congenitally deaf-mute, with recurrent syncopal events and a greatly prolonged QT c interval. The proband's mother and half-sister are both heterozygous for this mutation. Remarkably, both these family members have prolonged QT c intervals and would have been classified as Romano-Ward patients if not for the proband's diagnosis of JLN. This mutation was not identified in more than 100 control individuals. Conclusions-These data provide strong evidence that KCNE1 mutations represent a fifth LQTS locus (LQT5). Further functional analysis, as well as the identification of more LQTS patients with KCNE1 mutations, will be important to confirm the role of IsK in LQTS. (Circulation. 1998;97:142-146.) Key Words: arrhythmia Ⅲ genes Ⅲ molecular biology Ⅲ long-QT syndrome Ⅲ syncope L ong-QT syndrome (LQTS) is a rare cardiac disorder characterized by abnormal ventricular repolarization and a prolonged QT interval on the ECG. Clinically, two inherited forms of LQTS have been defined: autosomal dominant Romano-Ward syndrome 1,2 and autosomal recessive Jervell and Lange-Nielsen (JLN) syndrome.3 Patients with both Romano-Ward and JLN syndrome are predisposed to syncope, seizures, and sudden death, typically due to polymorphic ventricular tachycardia (torsade de pointes). In addition, the JLN syndrome is associated with congenital bilateral deafness, and these patients often have a more prolonged QT c on surface ECGs. Romano-Ward syndrome is genetically heterogeneous, with at least four different known loci. [4][5][6][7] Recently, homozygous mutations of one of these, KVLQT1, were reported to be responsible for JLN syndrome in three families. 8,9 However, it is also clear that the disease genes in certain JLN families are not linked to the KVLQT1 locus.10 Thus, JLN syndrome must also be a genetically heterogeneous group of clinically related disorders.IsK, an apparent potassium channel regulatory subunit encoded by the KCNE1 gene on chromosome 21, has recently been shown to coassemble with both K V LQT1, to produce the slowly activating cardiac delayed rectifier K ϩ current, I Ks , 11,12 and HERG, to regulate the rapidly activating ca...

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supporting

confidence: 66%

Mutation of the Gene for I sK Associated With Both Jervell and Lange-Nielsen and Romano-Ward Forms of Long-QT Syndrome

Duggal¹,

Vesely²,

et al. 1998

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“…The Kcne1 pkr /Kcne1 pkr mouse mutant has the profound bilateral deafness found with JLNS and the isk-null mouse, and common defects in the inner ear include the collapse of Reissner's membrane and loss of hair cells within the cochlea (Friedmann et al 1996;Vetter et al 1996). The I SK channels, composed of the KCNQ1 and KCNE1 gene products, are located at the apical membrane of the marginal cells of the stria vascularis and maintain a high potassium ion concentration within the endolymph, the fluid filling the scala media of the cochlea (Neyroud et al 1997).…”

Section: Discussionmentioning

confidence: 99%

A new spontaneous mouse mutation in the Kcne1 gene

Letts

Valenzuela

Dunbar

et al. 2000

Incorporating Mouse Genome

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A new mouse mutant, punk rocker (allele symbol Kcne1 pkr ), arose spontaneously on a C57BL/10J inbred strain background and is characterized by a distinctive head-tossing, circling, and ataxic phenotype. It is also profoundly and bilaterally deaf. The mutation resides in the Kcne1 gene on Chromosome (Chr) 16 and has been identified as a single base change within the coding region of the third exon. The C to T nucleotide substitution causes an arginine to be altered to a termination codon at amino acid position 67, and predictably this will result in a significantly truncated protein product. The Kcne1 pkr mutant represents the first spontaneous mouse model for the human disorder, Jervell and Lange-Nielsen syndrome, associated with mutations in the homologous KCNE1 gene on human Chr 21.

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“…This autosomal recessive association of profound childhood deafness with electrocardiographic abnormalities, fainting attacks and sudden death has been described by Jervell and Lange-Nielsen [17] in 1957. Salient histopathological features of this syndrome are the presence of PAS-positive hyaline nodules in or adjacent to the terminal vessels of the SV [18]. Recently, mutation of KVLQT1 and IsK genes encoding a potassium channel and a regulatory protein, respectively, has been reported [19][20][21].…”

Section: Congenital Deafnessmentioning

confidence: 99%

Endolymphatic Deafness: A Particular Variety of Cochlear Disorder

Huy¹

2002

ORL

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Experimental and clinical data made us consider some types of perceptive hearing loss secondary to an alteration of the secretory structures of the cochlea including stria vascularis, spiral ligament and supporting cells. These structures are responsible for the secretion of endolymph, a fluid characterized by a high potassium concentration (150–180 mM), a low sodium concentration (<1 mM) and a positive potential (80–100 mV). This intracellular-like fluid fills the endolymphatic compartment and is essential in the transduction process which takes place in the organ of Corti. Experimental studies have shown that drugs such as loop diuretics induced marked histological lesions in the stria vascularis and profound alterations in the electrochemical features of endolymph. Histopathological data have demonstrated that several entities such as prebyacusis, sudden deafness, and congenital or acquired progressive hearing loss could be related to strial abnormalities. Recent genetic studies have shown that a mutation of genes encoding connexins, a gap junction protein present in the secretory structures, was involved in some dominant or recessive forms of congenital deafness. Finally, the evaluation of labyrinthine fluids in humans has evidenced a decreased endocochlear potential in two cases of progressive flat hearing loss. All these arguments suggest that among the various types of so-called ‘sensorineural’ deafness, several entities including strial presbyacusis, diuretic-induced ototoxic deafness, some forms of congenital hearing loss and sudden deafness should be classified as endolymphatic deafness. Such an identification seems necessary since these entities result from different pathogenetic mechanisms, do not have the same evolution nor will they probably benefit from the same therapeutic management.

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Pathology of the Ear in the Cardio-Auditory Syndrome of Jervell and Lange-Nielsen (Recessive Deafness with Electrocardiographic Abnormalities)

Cited by 104 publications

References 16 publications

Mutation of the Gene for I sK Associated With Both Jervell and Lange-Nielsen and Romano-Ward Forms of Long-QT Syndrome

Mutation of the Gene for I sK Associated With Both Jervell and Lange-Nielsen and Romano-Ward Forms of Long-QT Syndrome

A new spontaneous mouse mutation in the Kcne1 gene

Endolymphatic Deafness: A Particular Variety of Cochlear Disorder

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