Fine mapping of a seizure susceptibility locus on mouse Chromosome 1: Nomination of Kcnj10 as a causative gene

被引：114

作者：

Ferraro T.N. ^{[1
,2
,6
]}

Golden G.T. ^{[1
,4
]}

Smith G.G. ^{[1
,4
]}

Martin J.F. ^{[1
,4
]}

Lohoff F.W. ^{[1
]}

Gieringer T.A. ^{[1
]}

Zamboni D. ^{[1
]}

Schwebel C.L. ^{[1
]}

Press D.M. ^{[1
]}

Kratzer S.O. ^{[1
]}

Zhao H. ^{[5
]}

Berrettini W.H. ^{[1
,3
]}

Buono R.J. ^{[1
]}

机构：

[1] Department of Psychiatry, University of Pennsylvania, Philadelphia

[2] Department of Pharmacology, University of Pennsylvania, Philadelphia

[3] Department of Genetics, University of Pennsylvania, Philadelphia

[4] Research Service, Veterans Affairs Medical Center, Coatesville

[5] Center for Biostatistics, Dept. of Epidemiol. and Pub. Health, Yale University, New Haven

[6] University of Pennsylvania, Department of Psychiatry, Center for Neurobiology and Behavior, Philadelphia, PA 19104-6140

来源：

Mammalian Genome | 2004年 / 15卷 / 4期

关键词：

Quantitative Trait Locus; Mouse Chromosome; Congenic Strain; Inbred Mouse Strain; Seizure Susceptibility;

D O I：

10.1007/s00335-003-2270-3

中图分类号：

学科分类号：

摘要：

Previous quantitative trait loci (QTL) mapping studies document that the distal region of mouse Chromosome (Chr) 1 contains a gene(s) that is in large part responsible for the difference in seizure susceptibility between C57BL/6 (B6) (relatively seizure-resistant) and DBA/2 (D2) (relatively seizure-sensitive) mice. We now confirm this seizure-related QTL (Szs1) using reciprocal, interval-specific congenie strains and map it to a 6.6-Mb segment between Pbx1 and D1Mit150. Haplotype conservation between strains within this segment suggests that Szs1 may be localized more precisely to a 4.1-Mb critical interval between Fcgr3 and D1Mit150. We compared the coding region sequences of candidate genes between B6 and D2 mice using RT-PCR, amplification from genomic DNA, and database searching and discovered 12 brain-expressed genes with SNPs that predict a protein amino acid variation. Of these, the most compelling seizure susceptibility candidate is Kcnj10. A survey of the Kcnj10 SNP among other inbred mouse strains revealed a significant effect on seizure sensitivity such that most strains possessing a haplotype containing the B6 variant of Kcnj10 have higher seizure thresholds than those strains possessing the D2 variant. The unique role of inward-rectifying potassium ion channels in membrane physiology coupled with previous strong association between ion channel gene mutations and seizure phenotypes puts even greater focus on Kcnj10 in the present model. In summary, we confirmed a seizure-related QTL of large effect on mouse Chr 1 and mapped it to a finely delimited region. The critical interval contains several candidate genes, one of which, Kcnj10, exhibits a potentially important polymorphism with regard to fundamental aspects of seizure susceptibility.

引用

页码：239 / 251

页数：12

共 48 条

[31]

Letts V.A., Felix R., Biddlecome G.H., Arikkath J., Mahaffey C.L., Et al., The mouse stargazer gene encodes a neuronal Ca2+-channel subunit, Nat Genet, 19, pp. 340-346, (1998)

[32]

Marcus D.C., Wu T., Wangemann P., Kofuji P., KCNJ10 (Kir4.1) potassium channel knockout abolishes endocochlear potential, Am J Physiol Cell Physiol, 282, (2002)

[33]

Moseley A.E., Lieske S.P., Wetzel R.K., Fames P.F., He S., Et al., The Na,K-ATPase alpha 2 isoform is expressed in neurons, and its absence disrupts neuronal activity in newborn mice, J Biol Chem, 278, pp. 5317-5324, (2003)

[34]

Nadeau J.H., Frankel W.N., The roads from phenotypic variation to gene discovery: Mutagenesis versus QTLs, Nat Genet, 25, pp. 381-384, (2000)

[35]

Neusch C., Rozengurt N., Jacobs R.E., Lester H.A., Kofuji P., Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination, J Neurosci, 21, pp. 5429-5438, (2001)

[36]

Patil N., Cox D.R., Bhat D., Faham M., Myers R.M., A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation, Nat Genet, 11, pp. 126-129, (1995)

[37]

Sambrook J., Fritsch E.F., Maniatis T., Ed., (1989)

[38]

Schlesinger K., Boggan W.O., Griek B.J., Pharmacogenetic correlates of pentylenetetrazol and electroconvulsive seizure thresholds in mice, Psychopharmacology, 13, pp. 181-188, (1968)

[39]

Signorini S., Liao Y.J., Duncan S.A., Jan L.Y., Stoffel M., Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K channel GIRK2, Proc Natl Acad Sci USA, 94, pp. 923-927, (1997)

[40]

Singh N.A., Charlier C., Stauffer D., DuPont B.R., Leach R.J., Et al., A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns, Nat Genet, 18, pp. 25-29, (1998)

← 1 2 3 4 5 →