Spasmodic, a mutation on chromosome 11 in the mouse

Abstract

A new recessive mutation, spasmodic (spd), producing behavior that mimics that of the neurological mutation spastic (spa) with rapid tremors, stiff posture, and difficulty in righting, arose spontaneously in strain A/HeJ at the Jackson Laboratory in 1979. It is not an allele of spa and linkage tests show that this mutation is located close to vestigial tail (vt) near the center of chromosome 11. Additional genetic tests show that it is not an allele of trembler (Tr), shaker-2 (sh-2), nor vibrator (vb), all neurological mutations located in the same region of chromosome 11. No differences were observed in the levels of the major CNS and PNS myelin proteins or lipids of spd/spd mice versus littermate controls, suggesting that, unlike several closely linked mutations, the spd mutation does not affect myelination. Pharmacological studies reported here show that aminooxyacetic acid improves the behavioral abnormalities of affected spd/spd mice in the same way it improves the behavior of affected spa/spa mice. However, unlike the spa/spa mice, there are no changes in the postsynaptic receptors for glycine, GABA, or benzodiazepines in spd/spd mice.

Molecular dissection of a contiguous gene syndrome: frequent submicroscopic deletions, evolutionarily conserved sequences, and a hypomethylated "island" in the Miller-Dieker chromosome region.

“…Our results extend this remarkable homology by an additional 30 centimorgans on the human map, to the terminal portion of human 17p. Knowledge of the chromosomal location in mouse and the extensive homology between human chromosome 17 and mouse chromosome 11 may facilitate a search for a mouse model for MDS, as at least seven neurological mutants are known on mouse chromosome 11 (25,26).…”

Distinct Physiological Mechanisms Underlie Altered Glycinergic Synaptic Transmission in the Murine Mutantsspastic,spasmodic, andoscillator

“…This reduces GlyR levels in the spinal cord and brainstem (White and Heller, 1982;Becker, 1990). In contrast, the spasmodic mouse (Lane et al, 1987) has a single point mutation (A52S) in the ␣1 subunit (Ryan et al, 1994;Saul et al, 1994). GlyR levels appear to be normal; however, agonist sensitivity is reduced (Ryan et al, 1994;Saul et al, 1994).…”

“…All three mutations are recessive disorders and homozygous affected animals exhibit a heightened "startle response," muscle rigidity, tremor, and impaired righting when disturbed (Chai, 1961;Lane et al, 1987;Buckwalter et al, 1994). In spastic mice (Chai, 1961), an intronic insertion of a LINE 1 transposable element in the GlyR ␤ subunit gene (Kingsmore et al, 1994;Mülhardt et al, 1994) causes exonskipping and decreased transcriptional efficiency of the ␤ subunit.…”

Chromosomal localization of glutamate receptor genes: relationship to familial amyotrophic lateral sclerosis and other neurological disorders of mice and humans.

“…Several of the murine GluR genes map close to loci that are defined by neurologic mutations. The Glur-l locus is localized to a region of mouse chromosome 11 in which the recessive vibrator (vb), shaker-2 (sh-2), tipsy (ti), and spasmodic (spd) mutations have been mapped (67)(68)(69)(70). Glur-2 maps to the region of mouse chromosome 3 that contains the spastic (sp) mutation; and Glur-7 maps to the region of mouse chromosome 4 that contains the clasper (cla) mutation (69,(71)(72)(73)(74).…”

“…In the spastic mouse, a large decrease in glycine receptors may be the primary cause of the disease (75). Spasmodic is a very similar phenotype, but it does not manifest changes in glycine receptor numbers (68). The Glur-6 gene maps close to circling mutants Jackson circler (jc) and waltzer (v) on mouse chromosome 10.…”