title: A novel intergenic ETnII-β insertion mutation causes multiple malformations in polypodia mice.
abstract: Mouse early transposon insertions are responsible for ~10% of spontaneous mutant phenotypes. We previously reported the phenotypes and genetic mapping of Polypodia, (Ppd), a spontaneous, X-linked dominant mutation with profound effects on body plan morphogenesis. Our new data shows that mutant mice are not born in expected Mendelian ratios secondary to loss after E9.5. In addition, we refined the Ppd genetic interval and discovered a novel ETnII-β early transposon insertion between the genes for Dusp9 and Pnck. The ETn inserted 1.6 kb downstream and antisense to Dusp9 and does not disrupt polyadenylation or splicing of either gene. Knock-in mice engineered to carry the ETn display Ppd characteristic ectopic caudal limb phenotypes, showing that the ETn insertion is the Ppd molecular lesion. Early transposons are actively expressed in the early blastocyst. To explore the consequences of the ETn on the genomic landscape at an early stage of development, we compared interval gene expression between wild-type and mutant ES cells. Mutant ES cell expression analysis revealed marked upregulation of Dusp9 mRNA and protein expression. Evaluation of the 5' LTR CpG methylation state in adult mice revealed no correlation with the occurrence or severity of Ppd phenotypes at birth. Thus, the broad range of phenotypes observed in this mutant is secondary to a novel intergenic ETn insertion whose effects include dysregulation of nearby interval gene expression at early stages of development.
authors: Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Jessica A
authors: JA
authors: Lehoczky
authors: Peedikayil E
authors: PE
authors: Thomas
authors: Kevin M
authors: KM
authors: Patrie
authors: Kailey M
authors: KM
authors: Owens
authors: Lisa M
authors: LM
authors: Villarreal
authors: Kenneth
authors: K
authors: Galbraith
authors: Joe
authors: J
authors: Washburn
authors: Craig N
authors: CN
authors: Johnson
authors: Bryant
authors: B
authors: Gavino
authors: Alexander D
authors: AD
authors: Borowsky
authors: Kathleen J
authors: KJ
authors: Millen
authors: Paul
authors: P
authors: Wakenight
authors: William
authors: W
authors: Law
authors: Margaret L
authors: ML
authors: Van Keuren
authors: Galina
authors: G
authors: Gavrilina
authors: Elizabeth D
authors: ED
authors: Hughes
authors: Thomas L
authors: TL
authors: Saunders
authors: Lesil
authors: L
authors: Brihn
authors: Joseph H
authors: JH
authors: Nadeau
authors: Jeffrey W
authors: JW
authors: Innis
mesh_terms: D000818:Animals; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000235:genetics; D002874:Chromosome Mapping; D004251:DNA Transposable Elements / Q000235:genetics*; D054637:Dual-Specificity Phosphatases / Q000235:genetics; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D050172:Genes, X-Linked; D051379:Mice; D016254:Mutagenesis, Insertional / Q000235:genetics*; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics*
chemical_list: D004251:DNA Transposable Elements; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; C517681:Pnck protein, mouse; D054637:Dual-Specificity Phosphatases; C484491:Dusp9 protein, mouse