Disease relevance of Glra1

• The commonest side-effects were dysphagia after treatment of spasmodic torticollis, weakness of neighbouring muscles after injections for hand cramps and breathiness and hypophonia following laryngeal injections [1].
• Resistance to botulinum toxin injections for spasmodic dysphonia [2].
• Naltrexone inhibits the persistent spasmodic dyskinesia induced by chronic intraperitoneal administration of iminodipropionitrile (IDPN) [3].
• The predominant overt signs of toxicity included an immediate and transient writhing reflex and/or persistent spasmodic myotwitching of the abdomen, and conspicuous suppression of orienting/exploratory behavior and emotional defecation [4].
• Coleus spp. have been used in Aurvedic medicine for heart diseases, spasmodic pain, painful micturition and convulsions [5].

High impact information on Glra1

• Here we describe a Glra1 missense mutation in spd that results in reduced agonist sensitivity in glycine receptors expressed in vitro [6].
• We conclude that spd is a murine homologue of hyperekplexia and that mutations in GLRA1/Glra1 can produce syndromes with different inheritance patterns [6].
• Here, we examined the in vivo relevance of Zn(2+) neuromodulation by producing knockin mice carrying the mutation D80A in the glycine receptor (GlyR) alpha1 subunit gene (Glra1) [7].
• A frameshift mutation in the mouse alpha 1 glycine receptor gene (Glra1) results in progressive neurological symptoms and juvenile death [8].
• Structure of a novel P-superfamily spasmodic conotoxin reveals an inhibitory cystine knot motif [9].

Biological context of Glra1

• Synteny homology and phenotypic similarities suggest that spasmodic mice may be a genetic model for the inherited human startle disease, hyperekplexia (STHE) [10].
• The resulting phenotype is similar to that of spasmodic [11].
• Spasmodic, a mutation on chromosome 11 in the mouse [12].
• The new Glra1 mutation appears to affect glycine's inhibitory neurotransmission in the central nervous system (CNS) of the nmf11 homozygotes, which suffer from a severe startle disease-related phenotype and die by postnatal day 21 [13].
• We examined the effects of the spa and ot mutations on GlyR- and GABAAR-mediated synaptic transmission in the superficial dorsal horn (SFDH), a spinal cord region where inhibition is important for nociceptive processing [14].

Anatomical context of Glra1

• As shown by [3H]strychnine binding and western blot analysis employing subunit-specific antibodies, spinal cord of homozygous oscillator mice was totally devoid of alpha1-polypeptide, characterizing the Glra1(spd-ot) gene as a functional null allele of Glra1 [15].
• 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 [12].
• Alternatively, glycinergic tonic inhibition of sensitizing structures (e.g. the amygdala) in the wildtype may be diminished in spd/spd mutants, thus leading to a high sensitization level [16].

Associations of Glra1 with chemical compounds

• 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 [12].
• This alpha 1(A52S) mutant, in which a serine residue substitutes for alanine at amino acid 52, is responsible for the spasmodic phenotype in mice and alters the ability of glycine to activate the receptor [17].
• This "spasmodic" peptide has 27 amino acids, including two gamma-carboxyglutamate (Gla) residues [18].
• Clonidine and prazosin block the iminodipropionitrile (IDPN)-induced spasmodic dyskinetic syndrome in mice [19].

Other interactions of Glra1

• Although no recombination was observed between spd and Anx-6 or Glr-1, no evidence was obtained for a lesion in either gene [10].
• Patch-clamp recordings were performed from retinal slices of wild-type, GlyRalpha1-deficient (Glra1(spd-ot)) and GlyRalpha3-deficient (Glra3(-/-)) mice [20].

Analytical, diagnostic and therapeutic context of Glra1

• Sixteen patients suffering from spasmodic torticollis were selected: in 2 patients, BoNT/A treatment continued to be effective, in 9 patients, the treatment effect was impaired, and in 5 patients, secondary treatment failure developed [21].
• The C. gloriamaris spasmodic peptide has been synthesized, and the refolded polypeptide was shown to be biologically active using a mouse bioassay [9].
• Crystalline botulinum toxin type A was licensed in December 1989 by the Food and Drug Administration for treatment of certain spasmodic muscle disorders following 10 or more years of experimental treatment on human volunteers [22].
• Spastic (spa), spasmodic (spd), and oscillator (ot) mice have naturally occurring glycine receptor (GlyR) mutations, which manifest as motor deficits and an exaggerated "startle response." Using whole-cell recording in hypoglossal motoneurons, we compared the physiological mechanisms by which each mutation alters GlyR function [23].

References