title: Retrotransposon insertion in the T-cell acute lymphocytic leukemia 1 (Tal1) gene is associated with severe renal disease and patchy alopecia in Hairpatches (Hpt) mice.
abstract: "Hairpatches" (Hpt) is a naturally occurring, autosomal semi-dominant mouse mutation. Hpt/Hpt homozygotes die in utero, while Hpt/+ heterozygotes exhibit progressive renal failure accompanied by patchy alopecia. This mutation is a model for the rare human disorder "glomerulonephritis with sparse hair and telangiectases" (OMIM 137940). Fine mapping localized the Hpt locus to a 6.7 Mb region of Chromosome 4 containing 62 known genes. Quantitative real time PCR revealed differential expression for only one gene in the interval, T-cell acute lymphocytic leukemia 1 (Tal1), which was highly upregulated in the kidney and skin of Hpt/+ mice. Southern blot analysis of Hpt mutant DNA indicated a new EcoRI site in the Tal1 gene. High throughput sequencing identified an endogenous retroviral class II intracisternal A particle insertion in Tal1 intron 4. Our data suggests that the IAP insertion in Tal1 underlies the histopathological changes in the kidney by three weeks of age, and that glomerulosclerosis is a consequence of an initial developmental defect, progressing in severity over time. The Hairpatches mouse model allows an investigation into the effects of Tal1, a transcription factor characterized by complex regulation patterns, and its effects on renal disease.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Vishnu
authors.initials: V
authors.lastname: Hosur
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Cox
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Burzenski
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Riding
authors.forename: Lynn
authors.initials: L
authors.lastname: Alley
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Lyons
authors.forename: Anoop
authors.initials: A
authors.lastname: Kavirayani
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Martin
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Johnson
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
mesh_terms: D000505:Alopecia / Q000235:genetics; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004251:DNA Transposable Elements / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D007674:Kidney Diseases / Q000378:metabolism* / Q000821:virology; D051379:Mice; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013997:Time Factors; D014157:Transcription Factors; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004251:DNA Transposable Elements; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C489366:Tal1 protein, mouse