STOCK Elovl4^tm1Rayy/J

Stock number: 027977
Product name: E_mut+/-
Research areas: Dermatology Research, Developmental Biology Research, Research Tools, Sensorineural Research

Description

This Elovl4^del targeted mutation strain exhibits homozygous perinatal lethality, defective epidermal permeability barrier, and progressive retinal photoreceptor degeneration, and is useful in studies of Stargardt-like macular degeneration and progressive retinal degeneration.

Detailed description

The Elovl4 gene encodes a is required for the synthesis of very long chain saturated fatty acids and very long chain polyunsaturated fatty acids (chain length longer than C > 26). Mutations and small deletions in the human ELOVl4 gene are associated with Stargardt-like macular dystrophy (STGD3) and autosomal dominant Stargardt-like macular dystrophy (ADMD), also referred to as autosomal dominant atrophic macular degeneration. These mice carry a targeted mutation of the Elovl4 gene in which a 5bp deletion was introduced in exon 6, which is equivalent to a known human mutation. Mutant gene products (mRNA and protein) are detected by qRT-PCR and Western blot analysis of skin from homozygous pups. Mice that are heterozygous for the targeted mutation are viable and fertile. Homozygotes die a few hours after birth. At birth homozygous mice exhibit scaly, wrinkled skin, with severely compromised epidermal permeability barrier function. Heterozygotes have lower levels of long chain fatty acids in retinal tissue compared to wildtype controls. As early as 2 months of age, ultrastructural abnormalities are observed in cone photoreceptors. As the mice age, there is progressive accumulation of lipofuscin in retinal pigment epithelium (RPE) and subretinal deposits, debris in the subretinal space and vacuoles in the RPE. By 6 months, heterozygotes exhibit a significant loss of cone photoreceptors. In mutant mice 8 months in age, electroretinograms (ERGs) are abnormal, with elevated b- and a-wave amplitudes. At approximately 10 months of age, rod outer segments appear shortened.

Development

A targeting vector designed by Dr. Radha Ayyagari (University of Michigan) containing floxed NEO cassette was used to insert a 5 bp-deletion (AACTT) in exon 6 (using site-directed mutagenesis) of the Elovl4 gene. The construct was electroporated into unspecified 129/SvEv derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric animals were crossed to C57BL/6J mice. The floxed NEO cassette was removed by breeding the mice with a Cre deleter strain on the C57BL/6 background. The mice were crossed to C57BL/6J for one generation. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).

Allele

Symbol: Elovl4^tm1Rayy
Name: targeted mutation 1, Radha Ayyagari
MGI accession ID: MGI:3692750
Generation method: Targeted
Attributes: Hypomorph
Synonyms: E_mut^-; Elovl4^del
Marker symbol: Elovl4
Marker name: elongation of very long chain fatty acids (FEN1/Elo2, SUR4/Elo3, yeast)-like 4
Marker synonyms: ADMD; CT118; elongation of very long chain fatty acids (FEN1/Elo2, SUR4/Elo3, yeast)-like 4; ISQMR; SCA34; STGD2; STGD3
Chromosome: 9
Strain of origin: 129S/SvEv
Molecular note: A 5 bp deletion was engineered in exon 6. A floxed neo was included in the cassette and subsequently removed via cre expression. Western blot confirmed the presence of mutant protein.