B6.C3H(101)-In(2a;Itch)18H/LmatMmjax

Stock number: 033442
Product name: a^18H
Research areas: Dermatology Research, Immunology, Inflammation and Autoimmunity Research

Description

In(2a;Itch)18 or a^18H is chromosomal inversion on distal chromosome 2 that alters both the nonagouti (a) and Itch (itchy, E3 ubiquitin ligase) loci. Homozygous mice develop severe progressive immune disease and die between 6 and 8 months of age. These mice useful for studying autoimmune pathologies.

Detailed description

In(2a;Itch)18 or a^18H is a recessive radiation-induced mutation that resulted in a chromosomal inversion on distal chromosome 2. The inversion alters both the nonagouti (a) and Itch (itchy, E3 ubiquitin ligase) loci. Itch encodes an E3 ubiquitin ligase involved in erythroid and lymphoid cell differentiation and the regulation of immune responses. Mutations in Itch are associated with syndromic multisystem autoimmune disease. Nonagouti (a) encodes a paracrine signaling molecule involved in hair pigmentation. Heterozygous mice have a dark band down the back and homozygous mice are dark agouti with black pinna hairs. On the C57BL/6 background, homozygous In(2a;Itch)18 mice develop severe progressive immune disease and die between 6 and 8 months of age. Ulcerative dermatitis begins between 4-6 months of age. Homozygous mice exhibit pulmonary chronic interstitial inflammation, alveolar proteinosis, inflammation of the glandular stomach and skin, and hyperplasia of lymphoid cells, hematopoietic cells, and forestomach epithelium, as well as defects in both spermatogenesis and oogenesis. Some heterozygous animals display mild lymphoid hyperplasia in the spleen and lymph nodes but do not exhibit the lung or skin pathology seen in the homozygotes.

Development

The In(2a;Itch)18 inversion or a^18H was generated in an irradiated (C3H/HeH X 101/H)F1 male, however, additional analysis demonstrated that the mutation occurred in C3H/HeH. The male was mated to "tester" females carrying multiple coat color mutations and screened for mutations at each loci. The recessive a^18H mutation is a paracentric inversion on distal chromosome 2 that caused a deletion of 20 bp and 18 bp from the proximal and distal breakpoints, respectively. The inversion affects the nonagouti (a) and Itch (itchy, E3 ubiquitin ligase) loci. The inversion also contains the following genes: Raly, 8030497I0Rik, Eif2s2, Gm14226, Ahcy, and 2310005A03Rik. The distal breakpoint occurs between exons 1 and 2 of Itch, placing exon 2 distal to the breakpoint and exon 1 in the inverted region and near the proximal breakpoint. The inversion is believed to have removed the promoter region of Itch. Mice have been backcrossed to C57BL/6JNci for 27 generations. Upon arrival, mice were bred to C57BL/6J for at least one generation to establish the colony.

Allele

Symbol: In(2a;Itch)18H
Name: inversion, Chr 2, 18 Harwell
MGI accession ID: MGI:4822472
Generation method: Chemically and radiation induced
Synonyms: a^18H; Itch^-; Itch^a-18H; itchy; nonagouti 18 Harwell
Marker symbol: In(2a;Itch)18H
Marker name: inversion, Chr 2, 18 Harwell
Chromosome: 2
Strain of origin: C3H/HeH
Molecular note: This allele comprises a paracentric inversion that affects minimally two loci, agouti and Itch. A deletion of 18 and 20 bp from the proximal and distal breakpoints, respectively, occurred when the inversion was formed. Restriction digests of genomic clones suggests the distal breakpoint is located in intronic sequences between exons 1 (nts 1-98) and 2 (nts 99-189). Exon 2 of Itch was localized to within 600 bp distal to the inversion's distal breakpoint, placing exon 1 within the inverted region and near the proximal breakpoint. Exon trapping technology revealed that the distal breakpoint encompasses a novel E3 ubiqutin protein ligase. Northern analysis showed that this allele is missing a 5.1-kb message sequence when probed with Itch cDNA normally found in wild-type mice; the inversion event appears to have removed the promoter from the coding region of the Itch gene.
General note: This allele was induced in the presence of both X-rays and hydroxy urea.