High-resolution mapping of the sodium channel modifier Scnm1 on mouse chromosome 3 and identification of a 1.3-kb recombination hot spot

被引:12
作者
Buchner, DA
Trudeau, M
George, AL
Sprunger, LK
Meisler, MH
机构
[1] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA
[2] Vanderbilt Univ, Div Med Genet, Nashville, TN 37232 USA
关键词
modifier gene; neuromuscular disease; pre-mRNA splicing; Scn8a; Nav1.6; SNP;
D O I
10.1016/S0888-7543(03)00152-6
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Variation between inbred strains of mice can be used to identify modifier genes affecting the susceptibility to inherited disease. The med(J) allele of the sodium channel Scn8a contains a splice site mutation that results in sodium channel deficiency. The severity of the neurological disorder is determined by the modifier locus Scnm1. The wild-type allele of the modifier results in correct splicing of 10% of Scn8a(medj) pre-mRNA and a dystonic phenotype. The susceptible allele of the modifier in strain C57BL/6J results in 5% correctly spliced transcripts and a lethal phenotype. A mapping cross with C3H using 26 new markers and 2304 affected F2 animals localized the modifier gene to a 950-kb interval on mouse chromosome 3. Fine mapping of recombination breakpoints revealed a recombination hot spot of 1.3 kb. The ratio of genetic to physical distance in the hot spot is 85 cM/Mb, two orders of magnitude higher than the mouse genome average of 0.5 cM/Mb. The role of the modifier in other disorders in human and mouse can be tested with linked markers described here. (C) 2003 Elsevier Inc. All rights reserved.
引用
收藏
页码:452 / 459
页数:8
相关论文
共 36 条
[1]   Crossover breakpoint mapping identifies a subtelomeric hotspot for male meiotic recombination [J].
Badge, RM ;
Yardley, J ;
Jeffreys, AJ ;
Armour, JAL .
HUMAN MOLECULAR GENETICS, 2000, 9 (08) :1239-1244
[2]   Location of a major susceptibility locus for familiar schizophrenia on chromosome 1q21-q22 [J].
Brzustowicz, LM ;
Hodgkinson, KA ;
Chow, EWC ;
Honer, WG ;
Bassett, AS .
SCIENCE, 2000, 288 (5466) :678-682
[3]  
BUCHNER DA, 2003, IN PRESS GENE
[4]   Sodium channel Nav1.6 is localized at nodes of Ranvier, dendrites, and synapses [J].
Caldwell, JH ;
Schaller, KL ;
Lasher, RS ;
Peles, E ;
Levinson, SR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (10) :5616-5620
[5]   Variable levels of normal RNA in different fetal organs carrying a cystic fibrosis transmembrane conductance regulator splicing mutation [J].
Chiba-Falek, O ;
Parad, RB ;
Kerem, E ;
Kerem, B .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1999, 159 (06) :1998-2002
[6]   A locus for an autosomal dominant form of progressive renal failure and hypertension at chromosome 1q21 [J].
Cohn, DH ;
Shohat, T ;
Yahav, M ;
Ilan, T ;
Rechavi, G ;
King, L ;
Shohat, M .
AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 67 (03) :647-651
[7]   A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus -: and prevalence of variants in patients with epilepsy [J].
Escayg, A ;
Heils, A ;
MacDonald, BT ;
Haug, K ;
Sander, T ;
Meisler, MH .
AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 68 (04) :866-873
[8]   Resurgence of sodium channel research [J].
Goldin, AL .
ANNUAL REVIEW OF PHYSIOLOGY, 2001, 63 :871-894
[9]   A physical map of the mouse genome [J].
Gregory, SG ;
Sekhon, M ;
Schein, J ;
Zhao, SY ;
Osoegawa, K ;
Scott, CE ;
Evans, RS ;
Burridge, PW ;
Cox, TV ;
Fox, CA ;
Hutton, RD ;
Mullenger, IR ;
Phillips, KJ ;
Smith, J ;
Stalker, J ;
Threadgold, GJ ;
Birney, E ;
Wylie, K ;
Chinwalla, A ;
Wallis, J ;
Hillier, L ;
Carter, J ;
Gaige, T ;
Jaeger, S ;
Kremitzki, C ;
Layman, D ;
Maas, J ;
McGrane, R ;
Mead, K ;
Walker, R ;
Jones, S ;
Smith, M ;
Asano, J ;
Bosdet, I ;
Chan, S ;
Chittaranjan, S ;
Chiu, R ;
Fjell, C ;
Fuhrmann, D ;
Girn, N ;
Gray, C ;
Guin, R ;
Hsiao, L ;
Krzywinski, M ;
Kutsche, R ;
Lee, SS ;
Mathewson, C ;
McLeavy, C ;
Messervier, S ;
Ness, S .
NATURE, 2002, 418 (6899) :743-U3
[10]   An initiation site for meiotic crossing-over and gene conversion in the mouse [J].
Guillon, H ;
de Massy, B .
NATURE GENETICS, 2002, 32 (02) :296-299