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.
Highlights
Pseudoxanthoma elasticum in humans (PXE, OMIM#264800), an autosomal recessive Mendelian disorder, is characterized by multisystem ectopic mineralization with clinical manifestations primarily in the skin, the eyes, and the cardiovascular system [1,2]
A single-nucleotide polymorphism (SNP) in exon 14 in the Abcc6 gene displayed an A allele at base pair position 53,257,951 on chromosome 7 in KK/HlJ mice with vibrissae mineralization, and this SNP was subsequently shown to cause aberrant splicing of Abcc6 pre-mRNA, resulting in an out-of-frame mRNA transcript. This polymorphism was previously noted, with similar consequences on Abcc6 pre-mRNA splicing, in C3H/HeJ mice [9,10], and the presence of this polymorphism has been described in addition to C3H/HeJ in DBA/2J mice linked to dystrophic cardiac calcification (Dyscalc) phenotype [11]
Direct sequencing of exon 14 of the Abcc6 gene in the four inbred strains confirmed the presence of a homozygous A nucleotide in position c.1863, while C57BL/6J harbors a G in that position [8,9,10,11]
Summary
Pseudoxanthoma elasticum in humans (PXE, OMIM#264800), an autosomal recessive Mendelian disorder, is characterized by multisystem ectopic mineralization with clinical manifestations primarily in the skin, the eyes, and the cardiovascular system [1,2]. A characteristic finding in the targeted mutant mice is mineralization of the vibrissae dermal sheath, a connective tissue capsule surrounding the dermal bulb of vibrissae This mineralization develops in Abcc62/2 mice as early as 5–6 weeks of age and progresses with advancing age when the animals are fed normal laboratory diet [5,6]. A SNP in exon 14 (rs32756904) in the Abcc gene displayed an A allele at base pair position 53,257,951 on chromosome 7 in KK/HlJ mice with vibrissae mineralization, and this SNP was subsequently shown to cause aberrant splicing of Abcc pre-mRNA, resulting in an out-of-frame mRNA transcript This polymorphism was previously noted, with similar consequences on Abcc pre-mRNA splicing, in C3H/HeJ mice [9,10], and the presence of this polymorphism has been described in addition to C3H/HeJ in DBA/2J mice linked to dystrophic cardiac calcification (Dyscalc) phenotype [11]. Initial histopathologic examination of these mice revealed some evidence of mineralization in the dermal sheath of vibrissae in 129S1/SvImJ mice, while no mineralization was noted in C3H/HeJ and DBA/2J mice, when kept on standard rodent diet [8] (Table 1)
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