B6.C3Sn(Cg)-Clcc1^m1J/SlacJ

Stock number: 007723
Research areas: Neurobiology Research

Description

On the C57BL/6J background the Clcc1^m1J mutation causes endoplasmic reticulum stress in the cerebellum, progressive cerebellar granule cell loss, vacuoles in the inner granule layer, peripheral motor axon degeneration leading to late onset mild truncal ataxia and muscle wasting in the hind limbs.

Detailed description

The Clcc1^m1J mutation causes increased sensitivity to endoplasmic reticulum stress in the cerebellum, with granule cells having increased expression of Grp78 and accumulation of ubiquitinated protein. The phenotype caused by this mutation is more severe on this C57BL/6J background than on the C3H/HeSnJ background on which it arose. On this C57BL/6J congenic background homozygotes develop progressive cerebellar granule cell death and peripheral motor axon degeneration with late-onset peripheral neuropathy, ataxia and spasticity in the lower limbs. At 2 months of age homozygotes have low numbers of pyknotic granule cells in the inner granule cell layer, and at 11 and 17 months the inner granule layer of the rostral cerebellum has fewer than half the normal number of granule cells, and the caudal cerebellum has more variable and later onset degeneration. Vacuoles are found in the inner granule cell layer by 11 months of age and increase in size and number with age. By one year of age homozygotes develop mild truncal ataxia and muscle wasting in their hind limbs. This does not occur on the C3H/HeSnJ inbred strain, which is homozygous for this mutation, although C3H/HeSnJ do have pyknotic granule cells in the cerebellum by 2 months of age, and hypoplastic cerebellum with numerous vacuoles by 22 months of age.

Development

The Clcc1^m1J mutation was initially identified in a segregating stock containing B10.A-H2^a H2-T18^a/SgSnJ, C3H/HeSnJ, and C57BL/6NJ. This phenotype was backcrossed by backcross-intercross breeding onto the C57BL/6J background and sperm was cryopreserved from homozygous males at generation N6. It was subsequently determined that this mutation is a strain characteristic of the parental strain C3H/HeSnJ.

Allele

Symbol: Clcc1^m1J
Name: mutation 1, Jackson
MGI accession ID: MGI:5618134
Generation method: Spontaneous
Synonyms: nm2453; sprawler
Marker symbol: Clcc1
Marker name: chloride channel CLIC-like 1
Marker synonyms: ERAC1; Mclc; RP32
Chromosome: 3
Strain of origin: C3H/HeSnJ
Molecular note: The mutation is an intracisternal A-particle (IAP) retrotransposon insertion into a C3H/HeSnJ genomic region. The IAP is inserted into intron 2 of the gene and disrupts the normal splicing of the mRNA transcribed from this gene. Resulting in-frame stop codons from the insertion of IAP sequences resulted in severely reduced protein levels in mutant tissues. The retrotransposition of this IAP is a recent event occurring during, or after, the establishment of the C3H/HeSn substrain.