Rodent Lce gene clusters; new nomenclature, gene organization, and divergence of human and rodent genes.

TO THE EDITOR Human and rodent LCE gene clusters are located on the epidermal differentiation complexes (EDC; 1q21 in human, 3F2.1 in mouse and 2q34 in rat) and encode multiple small genes with similarities, particularly over their Nterminal region, to small proline-rich proteins. Many LCE genes contain the glycine–serine–cysteine-rich motif typical of cornified envelope proteins such as loricrin (Zhao and Elder, 1997; Marshall et al., 2001; Wang et al., 2001; Jackson et al., 2005). Their Nand C-termini are similar to known transglutaminase substrates and LCE proteins are demonstrated cornified envelope constituents (Marshall et al., 2001; Steinert et al., 2003). LCE proteins upregulate in the loricrin null mouse, suggesting that they can functionally substitute for loricrin (Koch et al., 2000; Hohl, 2005). We report here major dissimilarity between human and rodent LCE gene clusters, with a surprising level of divergence between mouse and rat. The human 17 gene LCE cluster comprises three major groups in three chromosomal clusters. Group members encode similar proteins with related expression patterns – thus human group 1 and 2 genes express mainly in external epithelia such as skin, whereas group 3 genes express usually in internal stratum corneum-forming epithelia (e.g. tongue surface) (Jackson et al., 2005). Recently, a nomenclature was agreed for the 17 human LCE genes (formerly XP5, EIG, SPRL, SPRRL, and LEP genes) (Jackson et al., 2005). We present here a related agreed nomenclature for mouse and rat Lce genes (Table 1 and Figure 1). All work reported here was institutionally approved. Rodent and human LCE gene expansion appears to have been largely independent (i.e. after the ancestral species diverged), and/or there has been rodent and human-specific gene homogenization after ancestral species divergence, probably via gene conversion. Rodents have 20–22 Lce genes, which cluster into two chromosomal groups (Figure 1). On the basis of conserved motifs rodent genes can be assigned into two groups (groups 1 and 3), which map to the two chromosomal clusters (Figure 1 and Figure S1). Rodent groups 1 and 3 are orthologs of human groups 1 and 3 (Figure S1; Jackson et al, 2005). However, individual rodent Lce genes cannot be assigned as direct orthologs of human LCE genes. For example, human LCE1A is not a direct ortholog of rodent Lce1a (or does not clearly derive from a recent common ancestor, see Figure S1). Rodent group 1 genes are characterized by an additional, variable length glycine–cysteine–serine cluster in their C-terminal portion, which is absent in human group 1 genes (Figure S1). The rodent group 1 expansion appears to be so recent that there is incomplete conservation between mouse and rat. The new nomenclature incorporates this difficulty as (1) clear mouse–rat orthologs have the same name (e.g. mouse and rat Lce1b appear to be orthologs; (2) paralogs (same species gene duplications) have an additional digit, for example, murine Lce1a1 and Lce1a2 probably derive from a gene duplication occurring after mouse and rat diverged (Figure 1 and Table 1); and (3) genes which appear structurally dissimilar have independent names. Rodents lack human group 2 LCEs (Figure S1; Jackson et al, 2005). The specific function of human group 2 proteins is unknown, although their expression in human keratinocytes is particularly calcium-sensitive and, like human group 1 proteins, they express in skin (Jackson et al., 2005; Su et al., 2004). Absence of group 2 rodent genes is accompanied by an expansion of group 1 genes relative to human (Table 1 and Figure 1). Human group 3 LCE genes and rodent group 3 Lce genes are structurally similar (Figure S1), cluster in a similar position on the genome in relationship to CRCT1/Crct1 (alias NICE-1/Nice1; Marenholz et al., 2001; Figure 1), and both groups are expressed strongly in internal epithelia (Su et al., 2004). We speculated that the major differences between human and rodent LCE genes may reflect the difference in stratum corneum and barrier requirements between hair-covered skin and sparsely haired skin. However, chimpanzee (a primate with hair-covered skin) contains LCE group 2 genes and their group 1 gene organization is similar to human (Chimpanzee Sequencing and Analysis Consortium, 2005). The surprising divergence in LCE chromosomal organization and protein coding sequences between species is consistent with the recent description of this gene cluster as an example of a