Partial loss of function of Clcc-1, an ER localized putative chloride channel, results in mild ER stress and slow progressing neurodegeneration in the NM2453 mouse strain.


Hagit Benyamini

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In: Summer Student Reports, 2011, Jackson Laboratory


The phenotype of a novel spontaneous mutant strain NM2453 reveals slow-progressing neurodegeneration of the cerebellar granule neurons, as well as peripheral neuropathy. Recent studies in Dr. Ackerman's lab have identified an intracisternal A particle (IAP) retrotransposon insertion in the Clcc-1 gene of this strain. So far, only one literature report on this gene exists and suggests that Clcc-1 is a putative subtype of chloride channel, expressed in the endoplasmic reticulum (ER) and the Golgi apparatus.

In this project we demonstrated that the endogenous human Clcc-1 is localized in/on the ER. In addition, mild ER stress was shown in the cerebellum of NM2453 mutant mice, as observed by activation of three ER stress-induced genes.

The AF0617 mouse strain, which contains a gene trap allele of the Clcc-1 gene, was also developed in Dr. Ackerman’s lab. While AF0617 heterozygous mice are viable and do not display neurodegeneration, AF0617 homozygous mice die at an early embryonic stage, implying that the AF0617 allele is a more severe allele of the Clcc1 gene. By crossbreeding NM2453 mice with AF0617 mice, we generated compound heterozygote, which were viable by E18.5 and displayed abnormal brain morphology.

Further research on the function of Clcc-1 may help us understand the molecular mechanism underlying neurodegeneration and early embryonic development.


Tel Aviv University, Israel

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