ARTICLE
The field of keratinization disorders has undergone an explosion of new
knowledge over the past few decades. The causes of some diseases have
now been identified at gene and molecular levels. To correlate molecular
biochemical events with morphological changes, it is necessary to detect
specific molecules with fine localization techniques, especially in electron
microscopic levels. A prerequisite for this is a set of reliable molecule-specific
probes and tissue-processing methods, that provide not only good morphology
but also good preservation of epitopes. Many antibodies against various
keratinization-associated molecules are now available. Reliable immunoelectron
microscopy methods with a variety of applications have been established
[1, 2]. With the aid of this approach, we and others have discovered unique
ultrastructural changes that are directly associated with the molecular
basis of keratinization disorders. Since technical aspects of recent advances
in electron microscopic immunocytochemistry in dermatology have been thoroughly
reviewed by Shimizu et al. [3], we focus on application of immunoelectron
microscopy in studies of normal and abnormal keratinization.
Normal keratinization
The process of epidermal differentiation or keratinization is characterized
by a series of morphological changes of keratinocytes. When basal keratinocytes
start to differentiate, they lose adhesion to the underlying basement
membrane, synthesize a new set of keratins, and become spinous cells.
The spinous cells then further differentiate and become granular cells
that contain keratohyalin granules. The differentiation from the granular
cells through the transitional cells to the cornified cells also involves
drastic morphological changes. The cells are flattened and lose their
nuclei, keratohyalin granules and most of other cellular organelles, while
establishing a structure called cornified cell envelopes beneath the plasma
membrane. This is a tightly regulated process, the molecular mechanisms
of which, however, are not fully understood.
Keratins
Keratins, the cytoplasmic intermediate filament proteins of epithelial
cells, are encoded by a multigene family and expressed in a tissue- and
differentiation-specific manner. They provide mechanical integrity to
cells including those in epidermis, oral mucosa and cornea. Keratins are
abundantly expressed in the epidermal keratinocytes and morphologically
visualized as tonofilaments. When the basal cells expressing K5 and K14
leave the basal compartment, they start to synthesize K1 and K10. Several
human diseases including epidermolytic hyperkeratosis (see below) have
now been identified as keratin disorders. In the stratum corneum, keratins
are compacted with filaggrin that is derived from profilaggrin stored
in keratohyalin granules (see below) [4]. Keratins are cross-linked with
cornified cell envelopes on the cell periphery as well. Arginine residues
of keratins, especially that of K1 are deiminated and converted to citrulline
residues by peptidylarginine deiminase(s) [5].
Profilaggrin/filaggrin
Profilaggrin is a large, insoluble, and highly phosphorylated protein
that consists of multiple filaggrin repeats flanked by N- and C-terminal
domains [6]. N-terminal domain is subdivided into A domain that contains
S100-like calcium binding domains and B domain of unknown function. Phosphorylation
occurs at multiple serine/threonine residues in each filaggrin repeat
[6, 7]. Profilaggrin is synthesized in the granular cell layer and localized
in keratohyalin granules (Fig.
1). Keratohyalin granules that contain profilaggrin are called
F-granules to be distinguished from L-granules that contain loricrin [8]
(see below).
During terminal differentiation, profilaggrin is dephosphorylated and
proteolytically processed into filaggrin monomers and terminal domains
[9-12]. Filaggrin functions as an intermediate filament-associated protein
that aggregates keratin filaments in the cornified cells [4]. This is
followed by conversion of basic arginine residues of filaggrin to citrulline
residues by peptidylarginine deiminase(s) [5]. Filaggrin is then hydrolyzed
into free amino acids.
The N-terminal domains are cleaved from the filaggrin repeats before
the formation of cornified cells and have a different fate from filaggrin
[12]. When the granular cells differentiate and become transitional cells,
the majority of the immunolabels for the N-terminal domains are translocated
from the keratohyalin granules to the nuclei [13] (Fig.
2). Although some labels are localized along the cornified cell
envelopes and in the cytoplasm [12], the finding of mostly nuclear localization
of the profilaggrin N-terminal domains suggests that these domains play
a role in the nuclear disintegration that occur before cornification.
Occurrence of parakeratosis in the absence of profilaggrin expression
commonly seen in many conditions including eczematous tissue reaction
and psoriasis vulgaris is consistent with this hypothesis. In this context
it is interesting that A domain contains two calcium binding motifs [14-
16], because calcium signals are closely associated with terminal differentiation
of keratinocytes.
Trichohyalin
Trichohyalin is a major structural protein of the inner root hair sheath
cells and the medulla of the hair shaft. It is thought to be sequentially
modified by peptidyl-arginine deiminase(s) and transglutaminases [17]
and serve as a keratin-intermediate filament matrix protein and/or a constituent
of the cell envelopes [18]. Trichohyalin, like profilaggrin, possesses
a pair of functional calcium-binding domains of the EF-hand type at its
N-terminus [18, 19]. The function of these domains is currently unknown.
Trichohyalin is occasionally expressed in the epidermis as well [20].
When present, the cells always co-express profilaggrin/filaggrin [21].
The biological significance of trichohyalin expression in normal keratinization
process is not clear at this moment.
Cornified cell envelopes
The cornified cell envelope is a highly insoluble sheath of protein
that accumulates adjacent to the interior surface of the keratinocyte
plasma membrane [22, 23]. Its external side is covered by a monomolecular
lipid layer, whereas its internal surface is linked to a keratin-rich
fibrous matrix that occupies the entire intracellular volume. It is assembled
via the action of transglutaminases that catalyze the formation of protein-protein
xi-(gamma-glutamyl)lysine cross-links. A variety of envelope component
proteins have been described, including involucrin, loricrin, small proline-rich
proteins, keratins, filaggrin, cystatin-A, elafin, and desmosomal proteins.
Formation of cell envelopes starts in the most superficial granular
cells or transitional cells [23]. Sequential changes in the morphology
of cell envelopes can be observed by immunoelectron microscopy. Involucrin
is expressed in the superficial spinous cells and appear to be cross-linked
to form an envelope scaffolding. The initial cell envelopes of about 15
nm in thickness are involucrin-positive (Fig.
3). Loricrin is expressed in the superficial granular cells and
cross-linked into the involucrin-rich scaffolding [24] (Fig.
4). Mature cell envelopes are involucrin-immunonegative, probably
due to antigen masking caused by extensive inter- and intra-molecular
cross-linking [24]. When expressed, loricrin first accumulates in L-granules
or distributes diffusely within the cells [8, 24]. Deposition of loricrin
along the cell membrane starts at the desmosomal attachment plaques [24,
25] (Fig. 4). Mature cell
envelopes are loricrin-positive except for desmosomal areas of the cell
envelopes. This is again likely due to antigen masking. In fact, trypsin
digestion of the skin sections can unmask the loricrin epitopes in the
desmosomal areas of the cell envelopes [25].
Nuclear DNA fragmentation
Keratinization, the typical tissue turnover process, has been regarded
as a programmed cell death [26-32]. Transitional cells between granular
cells and cornified cells show several features of apoptotic cells, such
as condensation of the cytoplasm and nuclear chromatin, fragmentation
of genomic DNA, and formation of cross-linked protein scaffold (cornified
cell envelopes) [13, 33]. As described above, N-terminal domains of profilaggrin
are translocated into the transitional cell nuclei. By combining immunoelectron
microscopy and terminal deoxynucleotidyl transferase-mediated dUDP nick-end
labeling (TUNEL) methods, we have demonstrated co-localization of fragmented
DNA and profilaggrin N-terminal domains in the condensed chromatin of
transitional cells [13] (Fig.
5).
Abnormal keratinization
As examples of abnormal keratinization, we chose psoriasis vulgaris,
epidermolytic hyperkeratosis, lamellar ichthyosis and loricrin keratoderma
and discuss immunoelectron microscopic findings and their etiological
significance.
Psoriasis vulgaris
Psoriasis vulgaris is a chronic, hyperproliferative and inflammatory
skin disorder of unknown etiology. Genetic factors are likely to be of
fundamental importance in the expression of the disease, although environmental
factors are also involved. In terms of keratinization, psoriatic epidermis
has served as an example of hyperproliferative abnormal keratinization.
Involucrin is expressed in the psoriatic epidermis, but late differentiation
markers such as profilaggrin and loricrin are greatly diminished or absent
[24, 34]. Decreased barrier functions have been detected in psoriatic
epidermis. In typical psoriatic epidermis, cell envelopes are formed precociously
and are persistently involucrin-immunoreactive [24, 35]. This suggests
that psoriatic cell envelopes remain in their premature stage without
further maturation. Expression of trichohyalin is abnormally increased
in psoriatic epidermis, that occurs in filaggrin-negative cells as well
as in positive cells [21]. The pathoetiological significance of this finding
is not known at this moment.
Epidermolytic hyperkeratosis
Epidermolytic hyperkeratosis or bullous congenital ichthyosiform erythroderma
is a congenital skin disease caused by mutations of the genes for keratins
K1 and K10 with dominant negative effects [36, 37]. Heterozygous mutations
in the rod-domain of keratin dominantly disrupt keratin network formation.
Keratin abnormalities have been suggested for many years based upon
electron microscopic analyses [38-40]. Keratin filament aggregation is
the earliest morphological abnormality to be recognized and precedes the
other distinct morphological changes such as cellular vacuolization and
formation of globular keratohyalin granules. This keratin abnormality
has also been observed in skin samples of affected fetuses during the
mid-trimester, even before the formation of keratohyalin granules and
stratum corneum [41, 42]. Clumping of keratin is distributed not only
in the suprabasal epidermal cells, but also in the infundibular part of
outer hair root sheaths, sebaceous ducts and sweat ducts, selectively
following the known distribution pattern of K1 and K10 [43]. Immunoelectron
microscopy has demonstrated that abnormally clumped keratins in the suprabasal
cells are composed of K1 and K10 [43] (Fig.
6). Keratin aggregations with similar morphology but different
distribution (mainly in the basal cells) have been detected in Dowling-Meara
type of epidermolysis bullosa simplex [44], the disease that turned out
to be a genetic disease of K5 and K14 [36, 37]. All these findings strongly
suggested underlying genetic abnormalities of K1 and K10 in epidermolytic
hyperkeratosis. This has been confirmed by identification of many K1/K10
mutations in patients.
Immunoelectron microscopy has also demonstrated that clumped keratins
are poorly associated with filaggrin [45]. This suggests that abnormal
compaction of keratin filaments in the cornified cell layer is responsible,
at least in part, for the thick stratum corneum or hyperkeratosis seen
in epidermolytic hyperkeratosis.
Lamellar ichthyosis (transglutaminase abnormality)
Defective cross-linking of the cell envelope and mutations of the transglutaminase
1 gene have been identified in patients with lamellar ichthyosis, an autosomal
recessive keratinization disorder [46-51]. Mice lacking the gene for transglutaminase
1 show erythrodermic skin with abnormal keratinization and impaired skin
barrier function [52]. Cornified cell envelopes are undetectable. Loricrin
is not cross-linked beneath the plasma membrane, but retained in the cytoplasm
as large aggregates (Fig. 7).
These findings clearly demonstrate that transglutaminase 1 is crucial
for cross-linking of cell envelope precursor proteins including loricrin.
Loricrin keratoderma
Loricrin keratoderma is a group of autosomal dominantly inherited skin
diseases caused by mutations of the loricrin gene [53]. The patients are
clinically diagnosed as ichthyotic variant of Vohwinkel's syndrome or
a variant of progressive symmetric erythrokeratoderma with palmoplantar
hyperkeratosis [54-58]. The patients show palmoplantar hyperkeratosis
with digital constriction and generalized ichthyosis or erythematous keratotic
plaques. So far five families with three different mutations have been
identified [54-58]. All mutations are heterozygous insertion mutations
of one nucleotide. Consequent frameshift alters the carboxyl terminus
into elongated missense sequences rich in arginine. We first discovered
abnormal distribution of loricrin in the patients' skin by immunoelectron
microscopy. When we used an antibody against C-terminus of wild type loricrin,
the staining was seen both in the cytoplasm and nucleoplasm. In contrast,
with an N-terminal loricrin antibody, that recognizes both mutant and
wild type loricrin, staining was much more intense in the nucleus than
in the cytoplasm [56] (Fig. 8).
This led us to speculate that mutant loricrin is preferentially translocated
into the nuclei. To confirm this, we raised antibody against the mutated
sequences of loricrin C-terminus and found that the patient's skin indeed
expresses mutant loricrin that is translocated into the nuclei [59].
Because loricrin-knockout mice show only transient erythroderma but
no hyperkeratosis [60], haploid insufficiency cannot explain the pathogenesis
of loricrin keratoderma. It is very likely that the loricrin mutations
have a dominant negative effect on the normal keratinization process particularly
on the nuclear functions. Electron microscopy and immunoelectron microscopy
have shown that parakeratotic cells in loricrin keratoderma have features
similar to those in apoptotic transitional cells [13]. If programmed cell
death or terminal differentiation of keratinocytes is hampered at a certain
stage, the final process of differentiation, i.e. sloughing off of the
dead horny cells from the skin surface, might also be affected. Cornified
cells remain adherent to each other and become hyperkeratotic. Although
the exact mechanisms are not clear, analyses of the mutant loricrin suggest
such a scenario.
CONCLUSION
This brief review emphasizes usefulness of immunoelectron microscopy
in understanding the pathoetiological mechanisms of keratinization disorders.
Immunoelectron microscopy continues to serve as one of the most useful
tools to see the consequences of genetic abnormalities in the field of
proteomics.
Acknowledgements
Our original studies cited here were supported in part by Grants-in-Aid
for Scientific Research from the Ministry of Education, Science, Sports
and Culture of Japan to AIY (10470184, 11877138), HT (08770618) and HI
(08457233, 10877130), and a grant from the Ministry of Health and Welfare,
Japan to HI.
Article accepted on 13/3/00
REFERENCES
1. Shimizu H, Ishida-Yamamoto A, Eady RAJ. The use of silver-enhanced
1-nm gold probes for light and electron microscopic localization of intra-
and extracellular antigens in skin. J Histochem Cytochem 1992;
40: 883-8.
2. Shimizu H, McDonald JN, Kennedy AR, Eady RAJ. Demonstration
of intra- and extracellular localization of bullous pemphigoid antigen
using cryofixation and freeze substitution for postembedding immunoelectron
microscopy. Arch Dermatol Res 1989; 281: 443-8.
3. Shimizu H, Nishikawa T. Recent advances in electron microscopic
immunocytochemistry in dermatology. Eur J Dermatol 1993; 3: 635-42.
4. Dale BA, Holbrook KA, Steinert PM. Assembly of stratum corneum
basic protein and keratin filaments in macrofibrils. Nature 1978;
276: 729-31.
5. Senshu T, Kan S, Ogawa H, Manabe M, Asaga H. Preferential
deimination of keratin K1 and filaggrin during the terminal differentiation
of human epidermis. Biochem Biophys Res Com 1996; 225: 712-9.
6. Dale BA, Resing KA, Presland RB. Keratohyalin granule proteins.
In: Leigh IM, Lane EB and Watt FM, eds. The keratinocyte handbook. Cambridge
University Press, Cambridge 1994: 323-50.
7. Resing KA, Johnson RS, Walsh KA. Mass spectrometric analysis
of 21 phosphorylation sites in the internal repeat of rat profilaggrin,
precursor of an intermediate filament associated protein. Biochem
1995; 34: 9477-8.
8. Steven AC, Bisher ME, Roop DR, Steinert PM. Biosynthetic pathways
of filaggrin and loricrin two major proteins expressed by terminally
differentiated epidermal keratinocytes. J Struct Biol 1990; 104:
150-62.
9. Resing KA, Walsh KA, Haugen-Scofield J, Dale BA. Identification
of proteolytic cleavage sites in the conversion of profilaggrin to filaggrin
in mammalian epidermis. J Biol Chem 1989; 264: 1837-45.
10. Kam E, Resing KA, Lim SK, Dale BA. Identification of rat
epidermal profilaggrin phosphatase as a member of the protein phosphatase
2A family. J Cell Sci 1993; 106: 219-26.
11. Resing KA, Dale BA, Walsh KA. Multiple copies of phosphorylated
filaggrin in epidermal profilaggrin demonstrated by analysis of tryptic
peptides. Biochemistry 1985; 24: 4167-75.
12. Presland RB, Kimball JR, Kautsky MB, Lewis SP, Lo CY, Dale
BA. Evidence for specific proteolytic cleavage of the N-terminal domain
of human profilaggrin during epidermal differentiation. J Invest Dermatol
1997; 108: 170-8.
13. Ishida-Yamamoto A, Takahashi H, Presland RB, Dale BA, Iizuka
H. Translocalion of profilaggrin N-terminal domain into keratinocyte nuclei
with fragmented DNA in normal human skin and loricrin keratoderma. Laboratory
Investigation 1998; 78: 1245-53.
14. Presland RB, Haydock PV, Fleckman P, Nirunsuksiri W, Dale
BA. Characterization of the human epidermal profilaggrin gene. Genomic
organization and identification of an S-100-like calcium binding domain
at the amino terminus. J Biol Chem 1992; 267: 23772-81.
15. Markova NG, Marekov LN, Chipev CC, Gan SQ, Idler WW, Steinert
PM. Profilaggrin is a major epidermal calcium-binding protein. Mol
Cell Biol 1993; 13: 613-25.
16. Presland RB, Bassuk JA, Kimball JR, Dale BA. Characterization
of two distinct calcium-binding sites in the amino-terminus of human profilaggrin.
J Invest Dermatol 1995; 104: 218-23.
17. Tarcsa E, Marekov LN, Andreoli J, Idler WW, Candi E, Chung
SI, Steinert PM. The fate of trichohyalin. Sequential post-translational
modifications by peptidyl-arginine deiminase and transglutaminases. J
Biol Chem 1997; 272: 27893-901.
18. Lee SC, Kim IG, Marekov LN, O'Keefe EJ, Parry DAD, Steinert
PM. The structure of human trichohyalin. Potential multiple roles as a
functional EF-hand-like calcium-binding protein, a cornified cell envelope
precursor, and an intermediate filament-associated (cross-linking) protein.
J Biol Chem 1993; 268: 12164-76.
19. Fietz MJ, McLaughlan CJ, Campbell MT, Rogers GE. Analysis
of the sheep trichohyalin gene: potential structural and calcium-binding
roles of trichohyalin in the hair follicle. J Cell Biol 1993; 121:
855-65.
20. Hamilton EH, Payne RE Jr., O'Keefe EJ. Trichohyalin: presence
in the granular layer and stratum corneum of normal human epidermis. J
Invest Dermatol 1991; 96: 666-72.
21. Ishida-Yamamoto A, Hashimoto Y, Manabe M, O'Guin WM, Dale
BA, Iizuka H. Distinctive expression of filaggrin and trichohyalin during
various pathways of epithelial differentiation. Br J Dermatol 1997;
137: 9-16.
22. Polakowska RR, Goldsmith LA. The cell envelope and transglutaminase.
In: Goldsmith LA, eds. Biochemistry, physiology and molecular biology
of the skin. Oxford University Press, New York, Oxford, 1991: 168-201.
23. Ishida-Yamamoto A, Iizuka H. Structural organization of cornified
cell envelopes and alterations in inherited skin disorders. Exp Dermatol
1998; 7: 1-10.
24. Ishida-Yamamoto A, Eady RAJ, Watt FM, Roop DR, Hohl D, Iizuka
H. Immunoelectron microscopic analysis of cornified cell envelope formation
in normal and psoriatic epidermis. J Histochem Cystochem 1996;
44: 167-75.
25. Ishida-Yamamoto A, Tanaka H, Nakane H, Takahashi H, Iizuka
H. Antigen retrieval of loricrin epitopes at desmosomal areas of cornified
cell envelopes: an immunoelectron microscopic analysis. Exp Dermatol
1999; 8: 402-6.
26. Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed
cell death in situ via specific labeling of nuclear DNA fragmentation.
J Cell Biol 1992; 119: 493-501.
27. McCall CA, Cohen JJ. Programmed cell death in terminally
differentiating keratinocytes: role of endogeneous endonuclease. J
Invest Dermatol 1991; 97: 111-4.
28. Haake AR, Polakowska RR. Cell death by apoptosis in epidermal
biology. J Invest Dermatol 1993; 101: 107-12.
29. Polakowska RR, Haake AR. Apoptosis: the skin from a new perspective.
Cell Death and Differentiation 1994; 1: 19-31.
30. Polakowska RR, Piacentini M, Bartlett R, Goldsmith LA, Haake
AR. Apoptosis in human skin develpment: morphogenesis, periderm, and stem
cells. Developmental Dynamics 1994; 199: 176-88.
31. Hockenbery DM, Zutter M, Hickey W, Nahm M, Korsmeyer SJ.
BCL2 protein is topographically restricted in tissues characterized by
apoptotic cell death. Proc Natl Acad Sci USA 1991; 88: 6961-5.
32. Ishida-Yamamoto A, Tanaka H, Nakane H, Takahashi H, Hashimoto
Y, Iizuka H. Programmed cell death in normal epidermis and loricrin keratoderma.
Multiple functions of profilaggrin in keratinization. J Invest Dermatol
Symposium Proceedings 1999; 4: 145-9.
33. Ishida-Yamamoto A, Yamauchi T, Tanaka H, Nakane H, Takahashi
H, Iizuka H. Electron microscopic in situ DNA nick end-labeling
in combination with immunoelectron microscopy. J Histochem Cytochem
1999; 47: 711-7.
34. Takahashi H, Kinouchi M, Tamura T, Iizuka H. Decreased beta2-adrenergic
receptor-mRNA and loricrin-mRNA, and increased involucrin-mRNA transcripts
in psoriatic epidermis: analysis by reverse transcription-polymerase chain
reaction. Br J Dermatol 1996; 134: 1065-9.
35. Ishida-Yamamoto A, Iizuka H. Differences in involucrin immunolabeling
within cornified cell envelopes in normal and psoriatic epidermis. J
Invest Dermatol 1995; 104: 391-5.
36. Irvine AD, McLean WHI. Human keratin diseases: the increasing
spectrum of disease and subtelty of the phenotype-genotype correlation.
Br J Dermatol 1999; 140: 815-28.
37. Fuchs E. Of mice and men: genetic disorders of the cytoskeleton.
Mol Biol Cell 1997; 8: 189-203.
38. Ishibashi Y, Klingmuller G. Erythrodermia ichthyosiformis
congenita bullosa Brocq. Uber die sogenannte granulose Degeneration. II.
Elektronenmikroskopische Untersuchungen der Basal- und Stachelzellschicht.
Arch Klin Exp Dermatol 1968; 232: 205-24.
39. Ishibashi Y, Klingmuller G. Erythrodermis ichthyosiformis
congenita bullosa Brocq. Uber die sognannte granulose Degeneration. V.
Elektronenmikroskopische Untersuchung der Blasenbildung und abschliessen
Besprechung. Arch Klin Exp Dermatol 1968; 233: 124-38.
40. Anton-Lamprecht I, Schnyder UW. Ultrastructure of inborn
errors of keratinization. VI. Inherited ichthyosis a model system
for heterogeneities in keratinization disturbance. Arch Derm Forsch
1974; 250: 207-27.
41. Holbrook KA, Dale BA, Sybert VP, Sagebiel RW. Epidermoloytic
hyperkeratosis: ultrastructure and biochemistry of skin and amniotic fluid
cells from two affected fetuses and a newborn infant. J Invest Dermatol
1983; 80: 222-7.
42. Eady RAJ, Gunner DB, Carbone LDL, Bricarelli FD, Gosden CM,
Rodeck CH. Prenatal diagnosis of bullous ichthyosiform erythroderma: detection
of tonofilament clumps in fetal epidermis and amniotic fluid cells. J
Med Genet 1986; 23: 46-51.
43. Ishida-Yamamoto A, McGrath JA, Judge MR, Leigh IM, Lane EB,
Eady RAJ. Selective involvement of keratins K1 and K10 in the cytoskeletal
abnormality of epidermolytic hyperkeratosis (Bullous Congenital Ichthyosiform
Erythroderma). J Invest Dermatol 1992; 99: 19-26.
44. Ishida-Yamamoto A, McGrath JA, Chapman SJ, Leigh IM, Lane
EB, Eady RAJ. Epidermolysis bullosa simplex (Dowling-Meara) is a genetic
disease characterized by an abnormal keratin filament network involving
keratins K5 and K14. J Invest Dermatol 1991; 97: 959-68.
45. Ishida-Yamamoto A, Eady RAJ, Underwood RA, Dale BA, Holbrook
KA. Filaggrin expression in epidermolytic ichthyosis (epidermolytic hyperkeratosis).
Br J Dermatol 1994; 131: 767-79.
46. Huber M, Rettler I, Bernasconi K, Frenk E, Lavrijsen SPM,
Ponec M, Bon A, Lautenschlager S, Schorderet DF, Hohl D. Mutations of
keratinocyte transglutaminase in lamellar ichthyosis. Science 1995;
267: 525-8.
47. Russell LJ, DiGiovanna JJ, Rogers GR, Steinert PM, Hashem
N, Compton JG, Bale SJ. Mutations in the gene for transglutaminase 1 in
autosomal recessive lamellar ichthyosis. Nature Genetics 1995;
9: 279-83.
48. Parmentier L, Blanchet-Bardon C, Nguyen S, Prud'homme JF,
Dubertret L, Weissenbach J. Autosomal recessive lamellar ichthyosis: identification
of a new mutation in transglutaminase 1 and evidence for genetic heterogeneity.
Hum Mol Genet 1995; 4: 1391-5.
49. Steller H. Mechanisms and genes of cellular suicide. Science
1995; 267: 1445-9.
50. Laiho E, Ignatius J, Mikkola H, Yee VC, Teller DC, Niemi
KM, Saarialho-Kere U, Palotie A. Transglutaminase 1 mutations in autosomal
recessive congenital ichthyosis: private and recurrent mutations in an
isolated population. Am J Hum Genet 1997; 61: 529-38.
51. Jeon S, Djian P, Green H. Inability of keratinocytes lacking
their specific transglutaminase to form cross-linked envelopes: absence
of envelopes as a simple diagnostic test for lamellar ichthyosis. Proc
Natl Acad Sci USA 1998; 95: 687-90.
52. Matsuki M, Yamashita F, Ishida-Yamamoto A, Yamad K, Kinoshita
C, Fushiki S, Ueda E, Morishima Y, Tabata K, Yasuno H, Hashida M, Iizuka
H, Ikawa M, Okabe M, Kondoh G, Kinoshita T, Takeda J, Yamanishi K. Defective
stratum corneum and early neonatal death in mice lacking the gene for
transglutaminase 1 (keratinocyte transglutaminase). Proc Natl Acad
Sci USA 1998; 95: 1044-9.
53. Ishida-Yamamoto A, Takahashi H, Iizuka H. Loricrin and human
skin disease: molecular basis of loricrin kratodermas. Histol Histopath
1998; 13: 819-26.
54. Maestrini E, Monaco AP, McGrath JA, Ishida-Yamamoto A, Camisa
C, Hovnanian A, Weeks DE, Lathrop M, Uitto J, Christiano AM. A molecular
defect in loricrin, the major component of the cornified cell envelope,
underlies Vohwinkel's syndrome. Nature Genet 1996; 13: 70-7.
55. Ishida-Yamamoto A, McGrath JA, Lam H, Iizuka H, Friedman
RA, Christiano AM. The molecular pathology of progressive symmetric erythrokeratoderma:
a frameshift mutation in the loricrin gene and perturbations in the cornified
cell envelope. Am J Hum Genet 1997; 61: 581-9.
56. Korge BP, Ishida-Yamamoto A, Punter C, Dopping-Hepenstal
PJC, Iizuka H, Stephenson AM, Eady RAJ, Munro CS. Loricrin mutation in
Vohwinkel's keratoderma is unique to the variant with ichthyosis. J
Invest Dermatol 1997; 109: 604-10.
57. Armstrong DKB, McKenna KE, Hughes AE. A novel insertional
mutation in loricrin in Vohwinkel's keratoderma. J Invest Dermatol
1998; 111: 702-4.
58. Takahashi H, Ishida-Yamamoto A, Kishi A, Ohara K, Iizuka
H. Loricrin gene mutation in a Japanese patient of Vohwinkel's syndrome.
J Dermatol Sci 1999; 19: 44-7.
59. Ishida-Yamamoto A, Takahashi H, Iizuka H. Mutant loricirn
is not crosslinked into the cornified cell envelopes but translocated
into the nuclei in loricrin keratoderma. J Invest Dermatol 1999;
112: 551.
60. de Viragh PA, Scharer L, Bundman D, Roop DR. Loricrin deficient
mice: upregulation of other cell envelope precursors rescues the neonatal
defect but fails to restore epidermal barrier function. J Invest Dermatol
1997; 108: 555.
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