PMC:1584416 / 13786-17106 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/1584416","sourcedb":"PMC","sourceid":"1584416","source_url":"http://www.ncbi.nlm.nih.gov/pmc/1584416","text":"Rescue of Progeroid Features in TTD Mice by Homozygous Lethal Xpd Alleles\nBecause patients with TTD, XPCS, and CS (but not XP) and the corresponding mouse models share similar accelerated progeroid symptoms [12,13,15,23], we next addressed ageing-related parameters in compound heterozygous mice (Figure 3). Whereas XpdTTD/TTD animals show reduced bone mineral density as an indication of the early onset of osteoporosis before ~14 mo of age [15], tail vertebrae from compound heterozygous XpdTTD/†XPCS mice were comparable to wt even at 20 mo of age (Figure 3B and 3C). Furthermore, whereas XpdTTD/TTD mice developed kyphosis earlier than wt animals (onset ~3 mo versus 12–20 mo), compound heterozygous XpdTTD/†XPCS mice did not (Figure 3B). Overall appearance and body weight curves revealed that TTD-associated age-related premature cachexia and lack of general fitness were fully rescued in compound heterozygous XpdTTD/†XPCS mice (Figure 3A and 3D). Finally, the life span of compound heterozygotes was extended relative to XpdTTD/TTD mice (Table 2).\nFigure 3 Rescue of TTD-Associated Segmental Progeroid Features in Compound Heterozygous Xpd TTD/†XPCS Mice\n(A) Photographs of 20-mo-old wt, compound heterozygous XpdTTD/†XPCS, and homozygous XpdTTD/TTD mice. Note the extreme cachexia (lack of subcutaneous fat) in the XpdTTD/TTD mouse and the absence of this phenotype in wt and XpdTTD/†XPCS mice.\n(B) Radiographs of 20-mo-old male wt, XpdTTD/†XPCS, and XpdTTD/TTD mice. Ageing XpdTTD/TTD mice develop kyphosis (curvature of the spinal column) and reduction of bone mineral density as shown in the 6–8 segment of the tail vertebrae counted from the pelvis (see close-up at right). Note the absence of these features in the XpdTTD / † XPCS mouse.\n(C) Quantification of relative bone mineral density of tail vertebrae from 20-mo-old male wt (n = 3), XpdTTD/†XPCS (n = 4), and XpdTTD/TTD (n = 3) mice. The p-values indicate the significance of the difference relative to XpdTTD/TTD. Error bars indicate SEM.\n(D) Body weight curves as a function of time. Note that the age-dependent cachexia observed in XpdTTD/TTD mice was rescued in both male and female XpdTTD / †XPCS mice. Significant differences between wt and XpdTTD/TTD but not between wt and XpdTTD/†XPCS mice were observed at 9 and 18 mo of age as indicated by asterisks. Error bars indicate SEM.\nTable 2 Pleiotropic Xpd Biallelic Effects in Mice and Cells To determine whether the homozygous lethal Xpd†XPCS allele was unique in its ability to ameliorate symptoms associated with the XpdTTD allele, we generated compound heterozygous XpdTTD/†XP mice by crossing the corresponding heterozygous animals. Similar to the Xpd †XPCS allele, the homozygous lethal Xpd †XP allele rescued cutaneous symptoms including hair loss (except locally during the first round; unpublished data), reduced cysteine content (cysteine index 9.3 ± 0.9 standard deviation [87% of wt], p = 0.01 versus TTD), ageing-associated premature cachexia (males and females were 36.1 ± 6.4 g [93% of wt] and 39.2 ± 3.2 g [116% of wt], respectively), and reduced life span (Table 2). Taken together, these data indicate that two independent alleles, which on their own are unable to support viability (Table 1), were nonetheless able to ameliorate TTD-associated phenotypes in vivo (Table 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