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Death occurs after a short period of physical retardation, characterized by
progressive weight loss and cachexia. Pathology of deceased mice failed to reveal
gross abnOlmalities and thus did not provide a clue to a cornmon cause of death,
During their life TID mice behaved quite normally, although repeatedly tremors
were noted, that were not observed in wt littermates, hinting at some neurological
deficit. We did not detect apparent CNS myelination abnormalities (analysis of the
nervus opticus and nervus ischiaticus).
Table 1. cysteine content and protein composition of wt and
TTD hair
wt TTD %ofwt
total cysteine content lOa,b (14t 7 (8) 70 (57)
IFd fraction 27 54 200
CRP fraction 66 39 59
HGT fraction 6 6 100
" All values represent percentages of total hair protein. b Values for cysteine
content represent the mean of three hair samples. C Typical values found for
control and TTD human hair (Kleijer et al., 1994) are indicated between
brackets. d IF, inter-mediate filament keratins; CRP, cysteine-rich matrix
Skin and hair abnormalities of TTD mice
The hallmark of TTD is the striking brittleness of hair and nails, due to a reduced
content of cysteine-rich matrix proteins, which crosslink the keratin filaments.
Newborn TID mice develop a normal coat (Figure 3a), but spontaneous hair loss
was first noted on the head around day 19 (Figure. 3b). Thereafter, a dramatic
progressive loss of hair continued until! at the age of four weeks, TTD mice had lost
most of their hair except for the whiskers and a small band of fur at the feet and tail
(Figure 3c). The naked condition lasted until the normal second cycle of hair growth
initiated, starting at the head region until a complete new coat was grown (Figure
3d). A few days later the hair loss began again and this cycle of hairloss and
regrowth was maintained throughout their life. However, since hair cycle synchrony
deteriorates later in life, hairloss became more patchy and not complete. To further
examine the hair defect, we performed scauning electron microscopy on skin of 4
week old TID mice, when most hairs were shed. Figure 3e shows, that broken TID
hair fibers terminate in brush ends and are (virtually) devoid of the typical cuticular
structure of nOlmal hair. Histological examination of the skin revealed follicular
plugging and dilation (data not shown). The reduction in cysteine-rich matrix
proteins (CRP, made up for up to 40% of cysteines) has a significant impact on the
overall cysteine content of TID hair. As apparent from Table 1, the cysteine content
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