RESUMEN

Jervell and Lange-Nielsen syndrome is an autosomal recessive form of long-QT syndrome. In addition to QT interval prolongation, this disorder is associated with congenital deafness. Jervell and Lange-Nielsen syndrome is rare, but affected individuals are susceptible to cardiac arrhythmias with a high incidence of sudden death and short life expectancy. A proband with Jervell and Lange-Nielsen syndrome and family members were ascertained and phenotypically characterized. Linkage, mutational, and DNA sequence analyses were used to define the genetic basis of this disorder. We found that the proband had long-QT syndrome and sensory deafness. Some family members also had QTc prolongation with an autosomal dominant pattern of inheritance, but these patients had normal hearing. The gene responsible for QTc prolongation in this family was mapped to chromosome 11p15.5 using linkage analyses. The maximum LOD score at D11S1318 was 5.46, indicating odds greater than 100,000:1 favoring linkage. Mutation analyses revealed a single base pair insertion in KVLQT11, the potassium channel gene responsible for chromosome 11-linked long-QT syndrome. This mutation caused a premature stop codon. All family members with QTc prolongation, except the proband, were heterozygous for the mutation. The proband with Jervell and Lange-Nielsen syndrome resulted from a consanguineous marriage and was homozygous for the KVLQT1 mutation. Homozygous mutation of KVLQT1 causes Jervell and Lange-Nielsen syndrome. Members of Jervell and Lange-Nielsen syndrome families should be examined for long-QT syndrome, even if they have normal hearing.

Asunto(s)

Cromosomas Humanos Par 11/genética , Sordera/genética , Síndrome de QT Prolongado/genética , Mutación , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Consanguinidad , Sordera/congénito , Genes Dominantes , Genes Recesivos , Heterocigoto , Homocigoto , Humanos , Lactante , Canales de Potasio KCNQ , Canal de Potasio KCNQ1 , Escala de Lod , Persona de Mediana Edad , Modelos Genéticos , Datos de Secuencia Molecular , Linaje , Polimorfismo Conformacional Retorcido-Simple , Análisis de Secuencia de ADN

RESUMEN

Supravalvular aortic stenosis (SVAS) is an inherited obstructive vascular disease that affects the aorta, carotid, coronary and pulmonary arteries. Previous molecular genetic data have led to the hypothesis that SVAS results from mutations in the elastin gene, ELN. In these studies, the disease phenotype was linked to gross DNA rearrangements (35 and 85 kb deletions and a translocation) in three SVAS families. However, gross rearrangements of ELN have not been identified in most cases of autosomal dominant SVAS. To define the spectrum of ELN mutations responsible for this disorder, we refined the genomic structure of human ELN and used this information in mutational analyses. ELN point mutations co-segregate with the disease in four familial cases and are associated with SVAS in three sporadic cases. Two of the mutations are nonsense, one is a single base pair deletion and four are splice site mutations. In one sporadic case, the mutation arose de novo. These data demonstrate that point mutations of ELN cause autosomal dominant SVAS.

Asunto(s)

Estenosis de la Válvula Aórtica/genética , Elastina/genética , Mutación , Clonación Molecular , Análisis Mutacional de ADN , Cartilla de ADN/genética , Femenino , Mutación del Sistema de Lectura , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Polimorfismo Conformacional Retorcido-Simple , Empalme del ARN

Asunto(s)

Sordera/genética , Síndrome de QT Prolongado/genética , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Cromosomas Humanos Par 11 , Análisis Mutacional de ADN , Sordera/congénito , Femenino , Ligamiento Genético , Homocigoto , Humanos , Lactante , Canales de Potasio KCNQ , Canal de Potasio KCNQ1 , Síndrome de QT Prolongado/congénito , Masculino , Persona de Mediana Edad , Mutación , Linaje

RESUMEN

The slowly activating delayed-rectifier K+ current, I(Ks), modulates the repolarization of cardiac action potentials. The molecular structure of the I(Ks) channel is not known, but physiological data indicate that one component of the I(Ks), channel is minK, a 130-amino-acid protein with a single putative transmembrane domain. The size and structure of this protein is such that it is unlikely that minK alone forms functional channels. We have previously used positional cloning techniques to define a new putative K+-channel gene, KVLQT1. Mutations in this gene cause long-QT syndrome, an inherited disorder that increases the risk of sudden death from cardiac arrhythmias. Here we show that KVLQT1 encodes a K+ channel with biophysical properties unlike other known cardiac currents. We considered that K(V)LQT1 might coassemble with another subunit to form functional channels in cardiac myocytes. Coexpression of K(V)LQT1 with minK induced a current that was almost identical to cardiac I(Ks). Therefore, K(V)LQT1 is the subunit that coassembles with minK to form I(Ks) channels and I(Ks) dysfunction is a cause of cardiac arrhythmia.

Asunto(s)

Miocardio/metabolismo , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/biosíntesis , Canales de Potasio/metabolismo , Secuencia de Aminoácidos , Animales , Células CHO , Células Cultivadas , Clonación Molecular , Cricetinae , ADN Complementario , Electrofisiología , Humanos , Canales de Potasio KCNQ , Canal de Potasio KCNQ1 , Datos de Secuencia Molecular , Oocitos , Técnicas de Placa-Clamp , Canales de Potasio/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Aminoácido , Transfección , Xenopus

RESUMEN

To identify genes important for human cognitive development, we studied Williams syndrome (WS), a developmental disorder that includes poor visuospatial constructive cognition. Here we describe two families with a partial WS phenotype; affected members have the specific WS cognitive profile and vascular disease, but lack other WS features. Submicroscopic chromosome 7q11.23 deletions cosegregate with this phenotype in both families. DNA sequence analyses of the region affected by the smallest deletion (83.6 kb) revealed two genes, elastin (ELN) and LIM-kinase1 (LIMK1). The latter encodes a novel protein kinase with LIM domains and is strongly expressed in the brain. Because ELN mutations cause vascular disease but not cognitive abnormalities, these data implicate LIMK1 hemizygosity in imparied visuospatial constructive cognition.

Asunto(s)

Cognición/fisiología , Proteínas de Unión al ADN/genética , Proteínas Serina-Treonina Quinasas/genética , Percepción Visual/genética , Síndrome de Williams/genética , Secuencia de Bases , Northern Blotting , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Encéfalo/fisiología , Aberraciones Cromosómicas , Cromosomas Humanos Par 7/genética , Elastina/genética , Eliminación de Gen , Regulación del Desarrollo de la Expresión Génica/fisiología , Humanos , Hibridación Fluorescente in Situ , Quinasas Lim , Datos de Secuencia Molecular , Fenotipo , Proteínas Quinasas/genética , Análisis de Secuencia de ADN , Dedos de Zinc/genética

RESUMEN

Deficiency of plasma platelet-activating factor (PAF) acetylhydrolase is an autosomal recessive syndrome that has been associated with severe asthma in Japanese children. Acquired deficiency has been described in several human diseases usually associated with severe inflammation. PAF acetylhydrolase catalyzes the degradation of PAF and related phospholipids, which have proinflammatory, allergic, and prothrombotic properties. Thus, a deficiency in the degradation of these lipids should increase the susceptibility to inflammatory and allergic disorders. Miwa et al. reported that PAF acetylhydrolase activity is absent in 4% of the Japanese population, which suggests that it could be a common factor in such disorders, but the molecular basis of the defect is unknown. We show that inherited deficiency of PAF acetylhydrolase is the result of a point mutation in exon 9 and that this mutation completely abolishes enzymatic activity. This mutation is the cause of the lack of enzymatic activity as expression in E. coli of a construct harboring the mutation results in an inactive protein. This mutation as a heterozygous trait is present in 27% in the Japanese population. This finding will allow rapid identification of subjects predisposed to severe asthma and other PAF-mediated disorders.

Asunto(s)

Asma/etiología , Fosfolipasas A/genética , Mutación Puntual , 1-Alquil-2-acetilglicerofosfocolina Esterasa , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Sitios de Unión , Mapeo Cromosómico , Humanos , Japón , Datos de Secuencia Molecular , Fosfolipasas/genética , Fosfolipasas A/deficiencia

RESUMEN

Genetic factors contribute to the risk of sudden death from cardiac arrhythmias. Here, positional cloning methods establish KVLQT1 as the chromosome 11-linked LQT1 gene responsible for the most common inherited cardiac arrhythmia. KVLQT1 is strongly expressed in the heart and encodes a protein with structural features of a voltage-gated potassium channel. KVLQT1 mutations are present in affected members of 16 arrhythmia families, including one intragenic deletion and ten different missense mutations. These data define KVLQT1 as a novel cardiac potassium channel gene and show that mutations in this gene cause susceptibility to ventricular tachyarrhythmias and sudden death.

Asunto(s)

Síndrome de QT Prolongado/genética , Canales de Potasio/genética , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas Humanos Par 11 , Clonación Molecular , Femenino , Ligamiento Genético , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Mutación Puntual , Polimorfismo Conformacional Retorcido-Simple , Alineación de Secuencia , Eliminación de Secuencia , Homología de Secuencia de Aminoácido

RESUMEN

To identify genes involved in vascular disease, we investigated patients with supravalvular aortic stenosis (SVAS), an inherited vascular disorder that causes hemodynamically significant narrowing of large elastic arteries. Pulsed-field gel and Southern analyses showed that a translocation near the elastin gene cosegregated with SVAS in one family. DNA sequence analyses demonstrated that the translocation disrupted the elastin gene and localized the breakpoint to exon 28. Taken together with our previous study linking SVAS to the elastin gene in two additional families and existing knowledge of vascular biology, these data suggest that mutations in the elastin gene can cause SVAS.

Asunto(s)

Estenosis de la Válvula Aórtica/genética , Elastina/genética , Secuencia de Aminoácidos , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Humanos Par 6 , Cromosomas Humanos Par 7 , Femenino , Ligamiento Genético , Humanos , Células Híbridas , Masculino , Datos de Secuencia Molecular , Linaje , Polimorfismo de Longitud del Fragmento de Restricción , Síndrome , Translocación Genética