title: Mouse models for pseudoxanthoma elasticum: genetic and dietary modulation of the ectopic mineralization phenotypes.
abstract: Pseudoxanthoma elasticum (PXE), a heritable ectopic mineralization disorder, is caused by mutations in the ABCC6 gene. Null mice (Abcc6(-/-) ) recapitulate the genetic, histopathologic and ultrastructural features of PXE, and they demonstrate early and progressive mineralization of vibrissae dermal sheath, which serves as a biomarker of the overall mineralization process. Recently, as part of a mouse aging study at The Jackson Laboratory, 31 inbred mouse strains were necropsied, and two of them, KK/HlJ and 129S1/SvImJ, were noted to have vibrissae dermal mineralization similar to Abcc6(-/-) mice. These two strains were shown to harbor a single nucleotide polymorphism (rs32756904) in the Abcc6 gene, which resulted in out-of-frame splicing and marked reduction in ABCC6 protein expression in the liver of these mice. The same polymorphism is present in two additional mouse strains, DBA/2J and C3H/HeJ, with similar reduction in Abcc6 protein levels, yet these mice did not demonstrate tissue mineralization when kept on standard rodent diet. However, all four mouse strains, when placed on experimental diet enriched in phosphate and low in magnesium, developed extensive ectopic mineralization. These results indicate that the genetic background of mice and the mineral composition of their diet can profoundly modulate the ectopic mineralization process predicated on mutations in the Abcc6 gene. These mice provide novel model systems to study the pathomechanisms and the reasons for strain background on phenotypic variability of PXE.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Haitao
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Chou
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Annerose
authors.initials: A
authors.lastname: Berndt
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Sundberg
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D004032:Diet; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011561:Pseudoxanthoma Elasticum / Q000235:genetics* / Q000503:physiopathology*; D013045:Species Specificity; D014738:Vibrissae / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C504743:Abcc6 protein, mouse