title: A de novo deafwaddler mutation of Pmca2 arising in ES cells and hitchhiking with a targeted modification of the Pparg gene.
abstract: We observed severe ataxia in mice homozygous for modification of the Pparg locus. Genetic analysis and nucleotide sequencing revealed that ataxia is caused by a T692K substitution in plasma membrane calcium ATPase 2 (Pmca2), which is tightly linked to Pparg, but not by modified PPARgamma itself. We traced this mutation and found that it arose spontaneously during clonal expansion of the targeted embryonic stem (ES) cells. Consistent with the deafwaddler phenotype in other Pmca2 mutants, homozygous T692K Pmca2 mutants exhibit severe balance disorder, impaired neurologic reflexes, and motor coordination, and have profound hearing loss. Heterozygous mutants have normal movement and motor function but are severely deficient in hearing. Our findings represent a cautionary example since, although rare, spontaneous mutations do arise in ES cells during culture and hitchhike onto the targeted gene mutation.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, 27599, USA.
authors.forename: Yau-Sheng
authors.initials: YS
authors.lastname: Tsai
authors.forename: Avani
authors.initials: A
authors.lastname: Pendse
authors.forename: Sheryl S
authors.initials: SS
authors.lastname: Moy
authors.forename: Ikuko
authors.initials: I
authors.lastname: Mohri
authors.forename: Antonio
authors.initials: A
authors.lastname: Perez
authors.forename: Jacqueline N
authors.initials: JN
authors.lastname: Crawley
authors.forename: Kinuko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000235:genetics*; D000252:Calcium-Transporting ATPases / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D034381:Hearing Loss / Q000235:genetics*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics*; D053499:Plasma Membrane Calcium-Transporting ATPases; D013234:Stem Cells / Q000166:cytology
chemical_list: D027682:Cation Transport Proteins; D047495:PPAR gamma; D053499:Plasma Membrane Calcium-Transporting ATPases; C506959:Atp2b2 protein, mouse; D000252:Calcium-Transporting ATPases