Target Discovery and Validation Reviews and Protocols

Keratin Transgenics and Knockouts 221
are responsible for the nail disorder PC type 2 and for the sebaceous gland
disorder steatocystoma multiplex (102). K17(–/–) mice do not develop a proper
fur coat during the first postnatal week. The alopecia is likely to be caused by
hair shaft fragility and apoptosis in the hair matrix cells being reverted within
the first postnatal hair cycle at 3 wk of age, coinciding with the presumably
compensatory upregulation of K16 (93). The alopecia detected in K17 null animals
was only featured in the mouse strain C57BL/6. The unexpected lack of a
nail pathology in K17 null mice was most recently explained by the expression
of K22 (3,36), which is a pseudogene in humans (3).
1.1.6. Lessons From Loss of Keratin Genes
and Redundant Expression of Other Family Members
The disruption of keratin IFs in the K5(–/–) and K18(–/–)/K19(–/–) mice
(21,63,64), their changed composition in K6a(–/–)/K6b(–/–) and K14(–/–)
mice (35,94,96) as well as the expression of dominant negative mutations in
K10 and K14 (72,81,85) generated phenotypes that were comparable.
However, the molecular mechanisms that might lead to cell and tissue fragility
are either diverging or not clarified yet. The absence, i.e., of the keratin K10
protein (75), has only subtle effects compared with the dramatic outcome of
the presence of a mutated (in this case, truncated) form of keratin K10 (81,85).
Often, an inserted mutation more readily leads to a disorganized and aggregated
keratin IFs than merely the loss of the corresponding keratin. Within
internal epithelia of the liver or pancreas, keratins are thought to be nonessential
cytoskeletal proteins but rather function as scaffolds, providing proper
topology for other accessory proteins (59,61). In some cases, certain keratins
can compensate for each other; in other cases they cannot. Keratin K19 seems
to fulfill the function of keratin K18 and vice versa, because they have the
same partner keratin K8 (34,61). In other cases, the substitution of K14 by K18
has only partially rescued the phenotypical outcome of the K14 deficiency in
mice (70), probably because of an inappropriate expression level compared
with its partner keratin K5. The replacement of K14 by a K16/K14 hybrid protein
seemed to achieve and expression level of the same abundance as the partner
keratin K5, which rescued the K14 phenotype to a large extent (100). With
respect to the genetic background in different mouse strains, there are many
deviations found in the resulting phenotypes of the keratin-deficient mice. The
K8 deficiency within the C57BL/6 background is 100% lethal, whereas the
loss of this keratin protein in FVB/N mice allows survival of ~30% of the
affected animals (53). Several different modifier genes might help to compensate
for the loss of a certain keratin in one strain, or there is a beneficial expression
profile of redundant keratins that help to overcome the often devastating
consequences of a vanished keratin.