Linkage of a Cardiac Arrhythmia, the Long QT Syndrome, and the Harvey
            <i>ras</i>
            -1 Gene

Keating, Mark T.; Atkinson, Donald L.; Dunn, Courtney M.; Timothy, Katherine W.; Vincent, G; Leppert, M.

doi:10.1126/science.1673802

Cited by 492 publications

(157 citation statements)

References 20 publications

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“…Subsequent discovery of an increased prevalence of a prolonged QT interval among healthy relatives of arrhythmic patients than among unrelated controls suggested heritability of this ECG trait in these families. Finally, using QT interval elongation as endophenotype allowed for successful genetic linkage studies (Keating et al, 1991;Keating and Sanguinetti, 2001). …”

Section: Biological Endophenotypesmentioning

confidence: 99%

Discovering Endophenotypes for Major Depression

Hasler

Drevets

Manji

et al. 2004

Neuropsychopharmacol

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739

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The limited success of genetic studies of major depression has raised questions concerning the definition of genetically relevant phenotypes. This paper presents strategies to improve the phenotypic definition of major depression by proposing endophenotypes at two levels: First, dissecting the depressive phenotype into key components results in narrow definitions of putative psychopathological endophenotypes: mood bias toward negative emotions, impaired reward function, impaired learning and memory, neurovegetative signs, impaired diurnal variation, impaired executive cognitive function, psychomotor change, and increased stress sensitivity. A review of the recent literature on neurobiological and genetic findings associated with these components is given. Second, the most consistent heritable biological markers of major depression are proposed as biological endophenotypes for genetic studies: REM sleep abnormalities, functional and structural brain abnormalities, dysfunctions in serotonergic, catecholaminergic, hypothalamic-pituitary-adrenocortical axis, and CRH systems, and intracellular signal transduction endophenotypes. The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiality, and clinical and biological plausibility. Finally, the case is made for the development of a new classification system in order to reduce the heterogeneity of depression representing a major impediment to elucidating the genetic and neurobiological basis of this common, severe, and often life-threatening illness.

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Section: Biological Endophenotypesmentioning

confidence: 99%

Discovering Endophenotypes for Major Depression

Hasler

Drevets

Manji

et al. 2004

Neuropsychopharmacol

1,022

739

View full text Add to dashboard Cite

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“…Long QT, characterized by ventricular arrhythmias resulting in recurrent fainting and sudden death, has been genetically linked to HRAS in 11p15.5 (Keating et al, 1991). Usher syndrome 1C (deafness, vestibular dysfunction, and progressive pigmentary retinopathy) and familial hyperinsulinism exhibit close genetic linkage with markers in 11p14-p15.1 Glaser et al, 1994).…”

mentioning

confidence: 99%

An Ordered NotI Fragment Map of Human Chromosome Band 11p15

et al. 1994

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“…Five loci have been mapped to chromosome 11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT3), 4q25-27 (LQT4), and 21q22-23 (LQT5). [1][2][3] The genes responsible for LQT1, LQT2, and LQT5 have been identified as cardiac potassium channel subunit genes (KVLQT1, HERG, KCNE1), 4 -8 respectively, and for LQT3 as a cardiac sodium channel gene (SCN5A). 9 Mutations in KVLQT1, recently renamed KCNQ1, 10 caused half of the LQTS 5,11,12 in all the previous cases studied.…”

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confidence: 99%

C-terminal HERG Mutations

et al. 1999

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Background —The long-QT syndrome (LQTS) is a genetically heterogeneous disease in which 4 genes encoding ion-channel subunits have been identified. Most of the mutations have been determined in the transmembrane domains of the cardiac potassium channel genes KCNQ1 and HERG . In this study, we investigated the 3′ part of HERG for mutations. Methods and Results —New specific primers allowed the amplification of the 3′ part of HERG , the identification of 2 missense mutations, S818L and V822 M, in the putative cyclic nucleotide binding domain, and a 1-bp insertion, 3108+1G. Hypokalemia was a triggering factor for torsade de pointes in 2 of the probands of these families. Lastly, in a large family, a maternally inherited G to A transition was found in the splicing donor consensus site of HERG , 2592+1G-A, and a paternally inherited mutation, A341E, was identified in KCNQ1 . The 2 more severely affected sisters bore both mutations. Conclusions —The discovery of mutations in the C-terminal part of HERG emphasizes that this region plays a significant role in cardiac repolarization. Clinical data suggests that these mutations may be less malignant than mutations occurring in the pore region, but they can become clinically significant in cases of hypokalemia. The first description of 2 patients with double heterozygosity associated with a dramatic malignant phenotype implies that genetic analysis of severely affected young patients should include an investigation for >1 mutation in the LQT genes.

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Linkage of a Cardiac Arrhythmia, the Long QT Syndrome, and the Harvey ras -1 Gene

Cited by 492 publications

References 20 publications

Discovering Endophenotypes for Major Depression

Discovering Endophenotypes for Major Depression

An Ordered NotI Fragment Map of Human Chromosome Band 11p15

C-terminal HERG Mutations

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