Disease relevance of Cm

• Mice heterozygous for the Jag1 null allele exhibit an eye dysmorphology similar to that of Cm /+ heterozygotes, but do not exhibit other phenotypes characteristic of Cm /+ mice or of humans with Alagille syndrome [1].
• Deletion map of the coloboma (Cm) locus on mouse chromosome 2 [2].
• The hyperkinesis is ameliorated by low doses of the psychostimulant D-amphetamine and can be rescued genetically by a transgene encoding SNAP-25, located within the Cm deletion [3].

Psychiatry related information on Cm

• The mouse mutant coloboma (Cm/+), which exhibits profound spontaneous hyperactivity and bears a deletion mutation on chromosome 2, including the gene encoding synaptosomal protein SNAP-25, has been proposed to model aspects of attention-deficit hyperactivity disorder [4].

High impact information on Cm

• These results establish the phenotype of Cm /+ mice as a contiguous gene deletion syndrome and demonstrate that Jag1 is essential for remodeling of the embryonic vasculature [1].
• Analysis of genomic DNA revealed that the Snap gene dosage in Cm/+ mice was 50% lower than control littermates [5].
• Evidence is presented that Sey is not allelic with Coloboma (Cm), another mutation affecting eye development on chromosome 2 [6].
• Glutamate release from and content in cortical synaptosomes of Cm/+ mice are greatly reduced, which might contribute to the learning deficits in these mutants [4].
• In dorsal striatum of Cm/+ mutants, but not ventral striatum, KCl-induced release of DA is completely blocked and that of 5-HT is significantly attenuated, suggesting that striatal DA and 5-HT deficiencies may be involved in hyperactivity [4].

Biological context of Cm

• There were no significant differences in dentate afferent-evoked population excitatory postsynaptic potential (pEPSP) slopes, pEPSP facilitation, or population spike (PS) amplitudes; however, paired-pulse inhibition of dentate PS amplitudes was significantly increased in Cm/+ mice [7].
• Mice heterozygous for the semidominant mutation coloboma (Cm/+) display several distinct pathologies including head bobbing, ophthalmic deformation, and locomotor hyperactivity [7].
• Furthermore, although brief high-frequency stimulation of the perforant path produced robust long-term potentiation (LTP) of synaptic responses in the dentate gyrus of +/+ mice, LTP was attenuated in Cm /+ mice [7].
• Both Cm and Dey show delayed detachment of the lens vesicle and microphthalmia, and homozygotes of both apparently die early in pregnancy [8].
• There were region-specific reductions in in vivo tyrosine hydroxylation and the DA metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum and nucleus accumbens of Cm/+ mice [9].

Anatomical context of Cm

• The Cm/+ mutation comprises a contiguous gene defect which encompasses deletion of the gene Snap encoding the presynaptic nerve terminal protein SNAP-25 that is an integral component of the synaptic vesicle docking and fusion complex [7].
• In situ hybridization analysis revealed that there were corresponding increases in tyrosine hydroxylase (TH) mRNA expression in noradrenergic cell bodies of the locus coeruleus of Cm/+ mice [10].
• The anterior chamber is usually present in Cm/+ [8].

Regulatory relationships of Cm

• Homozygotes do not survive beyond gestation day 6; heterozygotes (Cm/+) have a normal life-span but express reduced levels of SNAP-25 mRNA and protein in the brain [11].

Other interactions of Cm

• The Cm deletion mutation results in ophthalmic dysmorphology and behavioral deficits, including profound hyperactivity, and has been shown to encompass the gene Snap [2].
• The midpoint voltage for steady-state inactivation of LVA currents in Cm/+ was shifted in a depolarized direction by 8 mV before epilepsy onset, and the mean time constant for decay of LVA Ca2+ currents at -50 mV was also prolonged [12].
• EEG analysis of Coloboma (Cm/+), an autosomal dominant mutant mouse lacking one copy of the gene for a synaptosomal-associated protein (SNAP25) that interacts with HVA channels, reveals abnormal spike-wave discharges (SWDs) in the behaving animal [12].

Analytical, diagnostic and therapeutic context of Cm

• In situ hybridization data revealed that alpha(2A)-adrenergic receptor mRNA expression is upregulated in Cm/+ mice [10].
• The SNAP-25 deficient mouse mutant coloboma (Cm/+) is an animal model for investigating the biochemical basis of locomotor hyperactivity [10].

References