129S1.NON(NZO)-Col4a4^bwk/PgnJ

Stock number: 017865
Product name: bwk
Research areas: Internal/Organ Research

Description

Bwk (bilateral wasting kidneys) is a recessive mutation caused by a G to A point mutation in the Col4a4 (collagen, type IV, alpha 4) gene. Mice exhibit several characteristics of Alport Syndrome including glomerulosclerosis, albuminuria, tubular atrophy, tubulointerstitial nephritis and an accumulation of abnormal collagen in the glomerular basement membrane (GBM) as well as GBM lesions.

Detailed description

Bwk (bilateral wasting kidneys) is a spontaneous recessive mutation caused by a G to A point mutation in the first base of intron 30 of the Col4a4 (collagen, type IV, alpha 4) gene. The mutation maintains the mRNA reading frame, but skips exon 30 resulting in low levels of collagen α 3 α 4 α 5 (IV) trimers that are secreted and incorporated into the glomerular basement membrane. Col4a4 encodes as subunit of type IV collagen, a structural component of basement membranes. Mutations in Col4a4 are associated with type II autosomal recessive Alport Syndrome (hereditary glomerulonephropathy). Mice exhibit the following characteristics: progressive elevated ACR (albumin to creatinine ratio), glomerulosclerosis, inflammatory cell infiltration in the kidneys tubular atrophy, podocyte foot process effacement, and tubular protein casts. Similar to a subset of Alport syndrome patients, mice develop an accumulation of abnormal collagen in the glomerular basement membrane (GBM) as well as GBM lesions. No hearing or eye pathologies are detected.

Of the three genetic backgrounds tested, mice on the DBA/2J (Stock No. 014079) genetic background exhibit higher ACR, earlier onset of protein casts and inflammatory cell infiltration as compared to the original mixed NZO/NON background (Stock No. 005326) and mice on the 129S1/SvImJ background. However,kidneys develop severe end stage renal disease by 12 weeks of age in both the DBA/2J and 129S1 backgrounds. This strain may be useful for studying Alport Syndrome and abnormal collagen IV structure.

Development

The bilateral wasting kidneys (bwk) mutation arose spontaneously on the incipient recombinant congenic NONcNZO4/Lt (at N2F10) background at The Jackson Laboratory. This recessive mutation was first identified by a lean body type; it later was observed that mice developed chronic nephritis. The mutation was identified as a G to A point mutation in the first base of intron 30 of the Col4a4 (collagen, type IV, alpha 4) gene. The mutation occurred in the NON region of chromosome 1. Due to inbreeding depression mice of the recombinant congenic line were crossed to NON/ShiLtJ mice in order to succeed in maintaining it. Offspring of this cross were then intercrossed with N2F12 cousins to recover the bwk mutant subline. The mutant subline was then maintained by sibling inbreeding with cousin inbreeding in two generations. Sperm was cryopreserved from homozygous males at generation F45. The bwk allele was introgressed from NON;NZO-Col4a4^bwk/J (Stock No. 005326) to 129S1/SvImJ for 6 generations. During backcrossing, the Y chromosome was fixed to the 129S1/SvImJ genetic background. Sperm was cryopreserved from homozygous males in 2012.

Allele

Symbol: Col4a4^bwk
Name: bilateral wasted kidneys
MGI accession ID: MGI:4838011
Generation method: Spontaneous
Attributes: Hypomorph
Synonyms: bwk
Marker symbol: Col4a4
Marker name: collagen, type IV, alpha 4
Marker synonyms: [a]4(IV); ATS2; BFH; BFH1; CA44; E130010M05Rik
Chromosome: 1
Strain of origin: NONcNZO4/Lt
Molecular note: The mutation was identified as a G to A subsitition in the first base of intron 30. As a result exon 30 is skipped, however, the mRNA reading frame is maintained. Protein and immunohistochemical analysis indicates some alpha4 is produced and forms low levels of collagen IV (alpha3, alpha4, alpha5) trimers.