Genetic mapping and evaluation of candidate genes for spasmodic, a neurological mouse mutation with abnormal startle response.
Spasmodic (spd) is a recessive mouse mutation characterized by a prolonged righting reflex, fine motor tremor, leg clasping, and stiffness. Using an intersubspecific backcross that segregates spd, we placed spd on Chr 11 with the following gene order: Adra-1-3.8 +/- 2.1 cM-Pad-1-6.3 +/- 2.7-(spd, Anx-6, Csfgm, Glr-1, Il-3, Il-4, Il-5, Sparc)-9.1 +/- 2.4-D11 Mit5-2.2 +/- 1.5-Asgr-1. This localization eliminated the alpha 1-adrenergic receptor (Adra-1) and the alpha 1 and gamma 2 subunits of the GABAA receptor as candidate genes. Two other promising candidate genes, annexin VI (Anx-6) and a glutamate receptor (Glr-1), were mapped to within 2.1 cM of the spd locus. Although no recombination was observed between spd and Anx-6 or Glr-1, no evidence was obtained for a lesion in either gene. The presence of normal Anx-6 and Glr-1 mRNA transcripts was confirmed by Northern blot analysis, in situ hybridization, and DNA sequence analysis. The localization of Anx-6 and Glr-1 extends the known synteny homology between human chromosome 5q21-q31 and mouse Chr 11 and reveals the probable chromosomal location of the human counterpart to spd. Synteny homology and phenotypic similarities suggest that spasmodic mice may be a genetic model for the inherited human startle disease, hyperekplexia (STHE).
Buckwalter
M S
MS
Department of Human Genetics, University of Michigan Medical School, Ann Arbor 48109-0618.
Testa
C M
CM
Noebels
J L
JL
Camper
S A
SA
D017398:Alternative Splicing; D000818:Animals; D017317:Annexin A6 / Q000096:biosynthesis / Q000235:genetics*; D001483:Base Sequence; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism*; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D003433:Crosses, Genetic; D004569:Electroencephalography; D005072:Evoked Potentials, Auditory; D005260:Female; D015870:Gene Expression; D005808:Genes, Recessive; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008818:Mice, Neurologic Mutants / Q000235:genetics*; D008969:Molecular Sequence Data; D009043:Motor Activity; D009132:Muscles / Q000502:physiology*; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D013216:Reflex, Startle / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic
D017317:Annexin A6; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger