PMC:1584416 / 9845-13784 JSONTXT

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Because of a lack of available antibodies and the inability to distinguish amongst various mutant forms of XPD differing only by single amino acid substitutions, we were unable to ascertain the relative amount of XPD protein from the different alleles.\nDespite reduced levels of mRNA expression, the homozygous lethal Xpd†XPCS allele ameliorated multiple XpdTTD-associated disease symptoms in compound heterozygous XpdTTD/†XPCS animals including the hallmark brittle hair and cutaneous features fully penetrant in homo- and hemizygous TTD mice (Figure 2A–2C). In marked contrast to XpdTTD/TTD (and XpdTTD/KO) mice, which display complete hair loss in the first hair cycle and partial hair loss in subsequent cycles throughout their lives [21], compound heterozygous XpdTTD/†XPCS mice displayed some hair loss only during the first hair cycle and only locally at the back (Figure 2A). Scanning electron microscope analysis of XpdTTD/†XPCS hair revealed an almost normal appearance, with TTD-like features such as broken hairs found only at very low frequency (unpublished data). Amino acid analysis confirmed that cysteine levels in the hair of the XpdTTD/†XPCS mice were significantly higher than in XpdTTD/TTD animals, but remained below the wt level (Figure 2C). TTD hemizygotes (XpdTTD/KO) do not display significant differences in cutaneous features and longevity relative to homozygous XpdTTD/TTD mice [21].\nFigure 2 Partial Rescue of TTD Cutaneous, Blood, and Developmental Phenotypes in Compound Heterozygous XpdTTD/†XPCS Mice\n(A) Photographs of 5-mo-old homozygous XpdTTD/TTD, compound heterozygous XpdTTD/†XPCS, and wt mice. Insets: images of first-round hair loss.\n(B) Histological analysis of the skin of XpdTTD/TTD, XpdTTD/†XPCS, and wt mice. TTD-associated acanthosis (thicker epidermis, indicated by solid vertical line), pronounced granular layer (indicated by arrows), and sebacious gland hyperplasia (indicated by dotted vertical line) were absent in the epidermis of XpdTTD/†XPCS and wt mice. Magnification 400×.\n(C) Cysteine content of hair from wt, XpdTTD/TTD, and XpdTTD/†XPCS mice. The p-value indicates significant differences between mutants and wt, as well as between XpdTTD/TTD and XpdTTD/†XPCS mice. Error bars indicate standard error of the mean (SEM).\n(D) Hematocrit values from blood of XpdTTD/TTD and XpdTTD/†XPCS mice. The p-values indicate the significance of the difference relative to wt. Error bars indicate SEM.\n(E) Body weights of developing XpdTTD/TTD and XpdTTD/†XPCS mice after weaning plotted as a percentage of the weight of age-matched control wt and heterozygote (hz) littermates (set at 100%). Error bars indicate SEM. Other prominent TTD features in the epidermis, including acanthosis (thickening of the layer of the nucleated cells), hyperkeratosis (prominent thickening of the cornified layer), and pronounced granular layer and sebacious gland hyperplasia (causing greasy appearance of the hair), were absent in the skin of XpdTTD/†XPCS mice, as established by blind microscopic examination of skin sections (Figure 2B). Furthermore, anaemia and developmental delay present in patients with TTD [24] and in XpdTTD/TTD mice [15] were both partially rescued in compound heterozygous XpdTTD/†XPCS mice (Figure 2D and 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