Two Dominant Mutations in the Mouse Fused Gene Are the Result of Transposon Insertions

Abstract

The mouse Fused locus encodes a protein that has been implicated in the regulation of embryonic axis formation. The protein, which has been named Axin to distinguish it from the product of the unrelated Drosophila melanogaster gene fused, contains regions of similarity to the RGS (regulators of G-protein signaling) family of proteins as well as to dishevelled, a protein that acts downstream of Wingless in D. melanogaster. Loss-of-function mutations at Fused lead to lethality between days 8 and 10 of gestation. Three dominant mutations result in a kinked tail in heterozygotes. Two of the dominant mutations, Fused and Knobbly, result from insertions of intracisternal A particle retrotransposons into the gene. The insertion in Fused, within the sixth intron, creates a gene that produces wild-type transcripts as well as mutant transcripts that initiate at both the authentic promoter and the 3′-most long terminal repeat of the insertion. Knobbly, an insertion of the retrotransposon into exon 7, precludes the production of wild-type protein. Thus the Fused homozygote is viable whereas Knobbly is a recessive embryonic lethal. In both mutants the dominant kink-tailed phenotype is likely to result from the synthesis of similar amino-terminal fragments of Axin protein that would contain the RGS domain, but lack the dishevelled domain.

Strain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans-Acting Modifiers

“…Metastable epialleles are regions of the genome which display variable epigenetic states between genetically identical individuals [77,78]. The most comprehensively studied metastable epialleles to date, A vy and Axin Fu , result from the variable silencing of IAP element insertions upstream of, or within, endogenous gene loci, and were identified due to observable phenotypic differences between littermates [79][80][81][82][83]. Whilst no strain-specific modifiers have been identified that specifically act on the IAP elements responsible for the A vy or Axin Fu alleles, it is clear that genetic background influences the heritability of these loci as well as the susceptibility of these alleles to environmental stimuli, two features for which these loci are particularly well known.…”

“…Similarly, the Axin Fu allele resulted from a spontaneous I∆1-type IAP element insertion in the sixth intron of Axin1 in the Bussey Institution stock of mixed genetic backgrounds [81,82] (Figure 3B, upper panel). At a low rate, the intronic IAP causes aberrant splicing, which results in both wild-type and mutant transcripts which contain the IAP; the inclusion of the Axin Fu IAP in the mRNA is predicted to generate a truncated AXIN1 protein [82] (Figure 3B, lower panel). Transcripts initiating within 100 bp downstream of the 3 LTR of the Axin Fu IAP have also been detected and may result in truncated peptides consisting of intron 6 and exons 7-10 [83].…”

“…Transcripts initiating within 100 bp downstream of the 3 LTR of the Axin Fu IAP have also been detected and may result in truncated peptides consisting of intron 6 and exons 7-10 [83]. The resultant kinked tail phenotype is attributed to the abnormal development of the posterior somites and axial duplications, which leads to vertebral fusions via atypical Wnt signalling [82,83]. Among isogenic individuals, tails range from kinked to completely normal, with the phenotypic severity inversely correlating with the DNA methylation status of the intronic Axin Fu IAP element [83] (Figure 3B, middle and lower panels).…”

Association Between AXIN1 Gene Polymorphisms and Epithelial Ovarian Cancer in Chinese Population

“…Subsequent research of AXIN in some human hepatocellular carcinomas and colorectal cancer (CRC), indicated that AXIN is a tumor suppressor gene [29,30]. AXIN1, instead of its homolog AXIN2, was demonstrated to be responsible for a series of dominant 'kinky' tail mouse phenotypes resulting from spontaneous transposon insertions into an Axin1 exon [31]. AXIN1 gene polymorphisms were associated with various diseases, such as clear cell renal cell carcinoma [14], gastrointestinal cancers [30], esophageal cancer [32], breast cancer as well as colon cancer [33,34] and so on.…”

Environmental Studies of Schizophrenia Through the Prism of Epigenetics

“…70 Axin Fu contains an IAP insertion in the intron 6 of the gene. 71 This causes the expression of a truncated Axin gene, which originates from the IAP insert, as well as the expression of the wild type gene, which results in a double dose of Axin during development. 72 This results in varying degrees of kinks in the tail of Axin Fu mice.…”