HGNC Approved Gene Symbol: IVL
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38) : 1:152,908,546-152,911,886 (from NCBI)
The crosslinked envelope of the keratinocyte is formed in the last stage of its terminal differentiation. This envelope is made up of membrane and cytosolic proteins crosslinked by glutamyl lysine isopeptide bonds. The most abundant component is involucrin, a keratinocyte protein that appears first in the cytoplasm but ultimately becomes crosslinked to membrane proteins by transglutaminase (summary by Eckert and Green, 1986).
Eckert and Green (1986) cloned the involucrin gene and studied its structure and evolution. The gene consists of 585 amino acids, 390 of which form a central decapeptide repeat, rich in glutamine and glutamic acid.
Teumer and Green (1989) described the divergent evolution of the IVL gene in gorilla and human.
Green and Djian (1992) reviewed the alterations in the involucrin gene during evolution of primates from nonprimates. As reflected in the 17 species examined, the changes involved short tandem repeats. Evolution of the IVL gene took place through mechanisms that shortened the length of the repeats, increased their number, and changed their codon sequence. As part of this trend, one entire segment of repeats was replaced by another located elsewhere in the coding region.
Green (1993) pointed to the relevance of the expanded poly(CAG) in the coding region of genes leading to 3 disorders: spinal and bulbar muscular atrophy (313200), Huntington disease (143100), and spinocerebellar ataxia type I (164400). Multiple glutamine residues, usually encoded by CAG, are necessary for the crosslinking of involucrin to other proteins by the keratinocyte transglutaminase during terminal differentiation in the keratinocytes with formation of the insoluble envelope of the corneocyte. Reiteration of the CAG codon appears to be very frequent. Of all the animal and plant protein sequences in 2 databases, Green (1993) found that 33 contained a sequence of 16 or more reiterated glutamines, but not one contained a run of more than 38 glutamines; hence, all showed a number of repeats lower than that in the abnormal alleles of the 3 human diseases of CAG reiteration. Therefore, reiteration must in some way be restricted in order to prevent genomic havoc.
The IVL gene has evolved rapidly in higher primates (Green and Djian, 1992). Djian et al. (1995) observed that, although all mammalian IVL genes examined to date possess a segment of short tandem repeats in the coding region, the higher primates possess a segment of repeats that is different from that of other mammals. This segment has enlarged progressively mainly in the region not far from the 5-prime end of the segment of repeats. The site of recent repeat additions is located in the late region, which is polymorphic with respect to number of repeats in most higher primates, including the human. The repeat pattern in the late region of the human IVL gene does not resemble that of other hominoids. Caucasians and Africans were found by Simon et al. (1991) and by Urquhart and Gill (1993) to differ in repeat patterns within this region and at certain nucleotide positions. Djian et al. (1995) observed that there are over 8 polymorphic forms based on the number and kind of 10-codon tandem repeats in that part of the coding region most recently added in the human lineage. The IVL alleles of Caucasians and Africans differ both in nucleotide sequence and repeat patterns. Djian et al. (1995) showed that the IVL alleles in East Asians (Chinese and Japanese) can be divided into 2 populations according to whether they possess the 2 marker nucleotides typical of Africans or Caucasians. The Asian population bearing Caucasian-type marker nucleotides had repeat patterns similar to those of Caucasians, whereas Asians bearing African-type marker nucleotides had repeat patterns resembling those of Africans more than those of Caucasians. The existence of 2 populations of East Asian IVL alleles gave support for the existence of a Eurasian stem lineage from which Caucasians and a part of the Asian population originated.
Lopez-Bayghen et al. (1996) characterized the 5-prime noncoding region of IVL and concluded that the region contains a distal CaCl(2)-responsive enhancer, a putative transcriptional silencer, and a proximal enhancer.
Stroh et al. (1987) used a genomic clone to probe a panel of human-rodent somatic cell hybrids and map the involucrin gene to chromosome 1. By in situ hybridization using the same probe, maximal hybridization was observed to bands 1q21-q22, with weak hybridization to 1p35-p36. They concluded that band 1q21 is the most likely location of the IVL gene. Simon et al. (1989) presented the data for mapping of the IVL gene. They also described a PstI RFLP, which they demonstrated in 1 individual to be the absence of 39 repeats that make up two-thirds of the coding region of the IVL gene. Simon et al. (1991) gave further information on the polymorphism in the coding region in the involucrin gene in higher primates, which results from the variable number of tandem repeats (VNTR) of a 10-codon sequence. Confirmation of the localization of the IVL gene to 1q21 was provided by Volz et al. (1993), who demonstrated physical linkage within 2.05 Mb of DNA to several other genes involved in epidermal differentiation and known to be located in that area.
Djian, P., Delhomme, B., Green, H. Origin of the polymorphism of the involucrin gene in Asians. Am. J. Hum. Genet. 56: 1367-1372, 1995. [PubMed: 7762559]
Eckert, R. L., Green, H. Structure and evolution of the human involucrin gene. Cell 46: 583-589, 1986. [PubMed: 2873896] [Full Text: https://doi.org/10.1016/0092-8674(86)90884-6]
Green, H. Human genetic diseases due to codon reiteration: relationship to an evolutionary mechanism. Cell 74: 955-956, 1993. [PubMed: 8104707] [Full Text: https://doi.org/10.1016/0092-8674(93)90718-6]
Green, H., Djian, P. Consecutive actions of different gene-altering mechanisms in the evolution of involucrin. Molec. Biol. Evol. 9: 977-1017, 1992. [PubMed: 1359382] [Full Text: https://doi.org/10.1093/oxfordjournals.molbev.a040775]
Lopez-Bayghen, E., Vega, A., Cadena, A., Granados, S. E., Jave, L. F., Gariglio, P., Alvarez-Salas, L. M. Transcriptional analysis of the 5-prime-noncoding region of the human involucrin gene. J. Biol. Chem. 271: 512-520, 1996. [PubMed: 8550612] [Full Text: https://doi.org/10.1074/jbc.271.1.512]
Simon, M., Phillips, M., Green, H. Polymorphism due to variable number of repeats in the human involucrin gene. Genomics 9: 576-580, 1991. [PubMed: 1674722] [Full Text: https://doi.org/10.1016/0888-7543(91)90349-j]
Simon, M., Phillips, M., Green, H., Stroh, H., Glatt, K., Burns, G., Latt, S. A. Absence of a single repeat from the coding region of the human involucrin gene leading to RFLP. Am. J. Hum. Genet. 45: 910-916, 1989. [PubMed: 2574003]
Stroh, H., Tseng, H., Harris, P., Bruns, G., Green, H., Latt, S. A. Chromosomal mapping of the human involucrin gene (IVL). (Abstract) Cytogenet. Cell Genet. 46: 700 only, 1987.
Teumer, J., Green, H. Divergent evolution of part of the involucrin gene in the hominoids: unique intragenic duplications in the gorilla and human. Proc. Nat. Acad. Sci. 86: 1283-1286, 1989. [PubMed: 2919176] [Full Text: https://doi.org/10.1073/pnas.86.4.1283]
Urquhart, A., Gill, P. Tandem-repeat internal mapping (TRIM) of the involucrin gene: repeat number and repeat-pattern polymorphism within a coding region in human populations. Am. J. Hum. Genet. 53: 279-286, 1993. [PubMed: 8317493]
Volz, A., Korge, B. P., Compton, J. G., Ziegler, A., Steinert, P. M., Mischke, D. Physical mapping of a functional cluster of epidermal differentiation genes on chromosome 1q21. Genomics 18: 92-99, 1993. [PubMed: 8276421] [Full Text: https://doi.org/10.1006/geno.1993.1430]