TEMPERATURE-SENSITIVE MUTATIONS IN THE III-IV-CYTOPLASMIC LOOP REGION OF THE SKELETAL-MUSCLE SODIUM-CHANNEL GENE IN PARAMYOTONIA-CONGENITA

被引:219
作者
MCCLATCHEY, AI
VANDENBERGH, P
PERICAKVANCE, MA
RASKIND, W
VERELLEN, C
MCKENNAYASEK, D
RAO, K
HAINES, JL
BIRD, T
BROWN, RH
GUSELLA, JF
机构
[1] MASSACHUSETTS GEN HOSP,DAY NEUROMUSCULAR RES,BOSTON,MA 02129
[2] HARVARD UNIV,SCH MED,BOSTON,MA 02129
[3] CATHOLIC UNIV LOUVAIN,CLIN UNIV ST LUC,DEPT NEUROL,B-1200 BRUSSELS,BELGIUM
[4] DUKE UNIV,DEPT MED,DIV NEUROSURG,DURHAM,NC 27706
[5] UNIV WASHINGTON,DEPT MED,SEATTLE,WA 98195
[6] UNIV CONNECTICUT,CTR HLTH,DEPT NEUROL,FARMINGTON,CT 06032
[7] SEATTLE VET AFFAIRS HOSP,DIV NEUROL,SEATTLE,WA 98195
关键词
D O I
10.1016/0092-8674(92)90151-2
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Paramyotonia congenita (PMC), a dominant disorder featuring cold-induced myotonia (muscle stiffness), has recently been genetically linked to a candidate gene, the skeletal muscle sodium channel gene SCN4A. We have now established that SCN4A is the disease gene in PMC by identifying two different single-base coding sequence alterations in PMC families. Both mutations affect highly conserved residues in the III-IV cytoplasmic loop, a portion of the sodium channel thought to pivot in response to membrane depolarization, thereby blocking and inactivating the channel. Abnormal function of this cytoplasmic loop therefore appears to produce the Na+ current abnormality and the unique temperature-sensitive clinical phenotype in this disorder.
引用
收藏
页码:769 / 774
页数:6
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