Kcnq1-5 (Kv7.1-5) potassium channel expression in the adult zebrafish

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Abstract

Background

KCNQx genes encode slowly activating-inactivating K ⁺ channels, are linked to physiological signal transduction pathways, and mutations in them underlie diseases such as long QT syndrome ( KCNQ1), epilepsy in adults ( KCNQ2/3), benign familial neonatal convulsions in children ( KCNQ3), and hearing loss or tinnitus in humans ( KCNQ4, but not KCNQ5). Identification of kcnqx potassium channel transcripts in zebrafish (Danio rerio) remains to be fully characterized although some genes have been mapped to the genome. Using zebrafish genome resources as the source of putative kcnq sequences, we investigated the expression of kcnq1-5 in heart, brain and ear tissues.

Results

Overall expression of the kcnqx channel transcripts is similar to that found in mammals. We found that kcnq1 expression was highest in the heart, and also present in the ear and brain. kcnq2 was lowest in the heart, while kcnq3 was highly expressed in the brain, heart and ear. kcnq5 expression was highest in the ear. We analyzed zebrafish genomic clones containing putative kcnq4 sequences to identify transcripts and protein for this highly conserved member of the Kcnq channel family. The zebrafish appears to have two kcnq4 genes that produce distinct mRNA species in brain, ear, and heart tissues.

Conclusions

We conclude that the zebrafish is an attractive model for the study of the KCNQ (Kv7) superfamily of genes, and are important to processes involved in neuronal excitability, cardiac anomalies, epileptic seizures, and hearing loss or tinnitus.

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Most cited references 43

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The zebrafish reference genome sequence and its relationship to the human genome.

Kerstin Howe, Matthew D. Clark, Carlos F Torroja … (2013)

Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.

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A systematic genome-wide analysis of zebrafish protein-coding gene function

Ross N W Kettleborough, Elisabeth Busch-Nentwich, Steven Harvey … (2013)

Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at an enormous rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in vertebrate model organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches 1-3 and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes 3,4 , this number falls significantly short of all >22,000 mouse protein-coding genes 5 . Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning 6 , insertional mutagenesis 7-9 , antisense morpholino oligonucleotides 10 , targeted re-sequencing 11-13 and zinc finger and TAL endonucleases 14-17 have made significant contributions to our understanding of the biological activity of vertebrate genes, but the number of genes studied again falls well short of the >26,000 zebrafish protein-coding genes 18 . Importantly, for both mice and zebrafish, none of these strategies is particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Enabled by a well-annotated zebrafish reference genome sequence 18,19 , high-throughput sequencing and efficient chemical mutagenesis, we describe an active project that aims to identify and phenotype disruptive mutations in every zebrafish protein-coding gene. Thus far we have identified potentially disruptive mutations in more than 38% of all known protein coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis.

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Prediction of human mRNA donor and acceptor sites from the DNA sequence.

S Brunak, J Engelbrecht, S. KNUDSEN (1991)

Artificial neural networks have been applied to the prediction of splice site location in human pre-mRNA. A joint prediction scheme where prediction of transition regions between introns and exons regulates a cutoff level for splice site assignment was able to predict splice site locations with confidence levels far better than previously reported in the literature. The problem of predicting donor and acceptor sites in human genes is hampered by the presence of numerous amounts of false positives: here, the distribution of these false splice sites is examined and linked to a possible scenario for the splicing mechanism in vivo. When the presented method detects 95% of the true donor and acceptor sites, it makes less than 0.1% false donor site assignments and less than 0.4% false acceptor site assignments. For the large data set used in this study, this means that on average there are one and a half false donor sites per true donor site and six false acceptor sites per true acceptor site. With the joint assignment method, more than a fifth of the true donor sites and around one fourth of the true acceptor sites could be detected without accompaniment of any false positive predictions. Highly confident splice sites could not be isolated with a widely used weight matrix method or by separate splice site networks. A complementary relation between the confidence levels of the coding/non-coding and the separate splice site networks was observed, with many weak splice sites having sharp transitions in the coding/non-coding signal and many stronger splice sites having more ill-defined transitions between coding and non-coding.

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Author and article information

Contributors

Calvin Wu

Kanishk Sharma

Kyle Laster

Mohamed Hersi

Christina Torres

Thomas J Lukas

Ernest J Moore

Journal

Journal ID (nlm-ta): BMC Physiol

Journal ID (iso-abbrev): BMC Physiol

Title: BMC Physiology

Publisher: BioMed Central

ISSN (Electronic): 1472-6793

Publication date Collection: 2014

Publication date (Electronic): 20 February 2014

Volume: 14

Page: 1

Affiliations

[1 ]Department of Molecular Pharmacology & Biological Chemistry, Northwestern University, Chicago, IL 60611, USA

[2 ]Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA

[3 ]Department of Speech & Hearing Sciences, University of North Texas, Denton, TX 76203, USA

Article

Publisher ID: 1472-6793-14-1

DOI: 10.1186/1472-6793-14-1

PMC ID: 4016485

PubMed ID: 24555524

SO-VID: fcef2915-1532-4745-9180-329e46f29b34

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

History

Date received : 25 June 2013

Date accepted : 11 February 2014

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Kcnq1-5 (Kv7.1-5) potassium channel expression in the adult zebrafish

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Abstract

Background

Results

Conclusions

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The Journal of Physiology

Most cited references 43

The zebrafish reference genome sequence and its relationship to the human genome.

A systematic genome-wide analysis of zebrafish protein-coding gene function

Prediction of human mRNA donor and acceptor sites from the DNA sequence.

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