Lamellar Ichthyosis: further narrowing, physical and expression mapping of the chromosome 2 candidate locus

Parmentier, Laurent; Clépet, Christian; Boughdene-Stambouli, Omar; Lakhdar, H.; Blanchet-Bardon, C; Dubertret, Louis; Wunderle, Edith; Pulcini, Françoise; Fizames, Cécile; Weissenbach, Jean

doi:10.1038/sj.ejhg.5200271

Cited by 32 publications

(26 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus we propose that the desmosome is an important site for the initiation of CE assembly. Furthermore, these observations have important implications for the disease lamellar ichthyosis caused by lack of a functional TGase 1 enzyme (33,(47)(48)(49). If the initiation of CE assembly as envisaged above cannot occur, we should expect profound problems with formation of an effective barrier, as it is clear that the TGase 2 and 3 enzymes also expressed in terminally differentiating keratinocytes which do not bind to membranes (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…This enzyme is of critical importance in skin barrier function in particular since mutations in its gene resulting in loss of activity cause the devastating life-threatening disease lamellar ichthyosis (47)(48)(49). Most of the TGase 1 enzyme resides on membranes through N-myristoyl and S-myristoyl or S-palmitoyl linkages (30 -32), although minor amounts dissociate to reside in the cytosol (46).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Involucrin Cross-linking by Transglutaminase 1

Nemes

Marekov

Steinert

1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

The transglutaminase 1 (TGase 1) enzyme is essential for the assembly of the cell envelope barrier in stratified squamous epithelia. It is usually bound to membranes, but to date most studies with it have involved solution assays. Here we describe an in vitro model system for characterizing the function of TGase 1 on the surface of synthetic lipid vesicles (SLV) of composition similar to eukaryote plasma membranes. Recombinant baculovirus-expressed human TGase 1 readily binds to SLV and becomes active in cross-linking above 10 M Ca 2؉ , in comparison to above 100 M in solution assays, suggesting that the membrane surface is important for enzyme function. Involucrin also binds to SLV containing 12-18% phosphatidylserine and at Ca 2؉ concentrations above 1 M. In reactions of involucrin with TGase 1 enzyme in solution, 80 of its 150 glutamines serve as donor residues. However, on SLV carrying both involucrin and TGase 1, only five glutamines serve as donors, of which glutamine 496 was the most favored. As controls, there was no change in specificity toward the glutamines of other substrates used by free or SLV-bound TGase 1 enzyme. We propose a model in which involucrin and TGase 1 bind to membranes shortly after expression in differentiating keratinocytes, but cross-linking begins only later as intracellular Ca 2؉ levels increase. Furthermore, the data suggest that the membrane surface regulates the steric interaction of TGase 1 with substrates such as involucrin to permit specific cross-linking for initiation of cell envelope barrier formation. The cell envelope (CE)1 is a highly insoluble structure assembled just inside the plasma membrane of stratified squamous epithelia and is essential for effective barrier function. To form the CE, specialized keratinocyte proteins are expressed and subsequently made insoluble by cross-linking by both disulfide bonds and isopeptide bonds formed by transglutaminases (TGases) (1-5).Emerging data suggest that the protein composition of CEs varies widely between epithelia and even different body sites of epithelia such as the epidermis (6, 7). However, involucrin seems to be a ubiquitous component of most if not all CEs. Indeed, several types of data imply that it is one of the first proteins to be cross-linked to initiate CE assembly. First, expression studies have revealed that involucrin deposition at the cell periphery precedes all other suspected or confirmed CE protein constituents (8 -15). Second, shadowing and scanning transmission electron microscopy suggest that a monomolecular layer of involucrin is overlayered on the cytoplasmic side by other CE structural proteins (16). Third, extant models of CE structure based on biochemical characterization and protein sequencing indicate that involucrin becomes cross-linked to several cell peripheral proteins including desmoplakin, envoplakin, keratin intermediate filaments, as well as other CE proteins including members of the small proline-rich family, cystatin ␣ and loricrin (6,17,18). Fourth, recent data have shown that invo...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Involucrin Cross-linking by Transglutaminase 1

Nemes

Marekov

Steinert

1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Furthermore, it is conceivable that mutations that affect directly those enzyme systems responsible for these post-synthetic modifications should result in a TGase 1 enzyme of greatly reduced specific activity or potential for proteolytic processing, with consequences of LI disease. In this regard, it is noteworthy that cases of CRI have been identified that do not involve mutations in the TGM1 gene (11)(12)(13). Further work must be done now to explore whether mutations in these ancillary gene systems, directly or indirectly affecting the TGase 1 enzyme, are the cause of CRI or LI disease.…”

Section: Discussionmentioning

confidence: 99%

“…Other clinical findings include palmar-plantar hyperkeratosis, eclabium, ectropion, scarring alopecia, and diminished skin barrier function. Recent studies have revealed marked biochemical (7,8) as well as genetic variations in CRI patients as follows: to date, in certain families, linkage has been described to chromosome regions 14q11 (9, 10), 2q33-35 (11), or to neither (11)(12)(13). However, all cases of the large brown plate scaling phenotype have been linked to 14q11, and several different mutations in the TGM1 gene located at this site have been identified (10, 11, 14 -15).…”

Section: Congenital Recessive Ichthyoses (Cri)mentioning

confidence: 99%

Transglutaminase 1 Mutations in Lamellar Ichthyosis

Candi¹,

Melino²,

Lahm³

et al. 1998

Journal of Biological Chemistry

View full text Add to dashboard Cite

Lamellar ichthyosis is a congenital recessive skin disorder characterized by generalized scaling and hyperkeratosis. It is caused by mutations in the TGM1 gene that encodes the transglutaminase 1 (TGase 1) enzyme, which is critical for the assembly of the cornified cell envelope in terminally differentiating keratinocytes. TGase 1 is a complex enzyme existing as both cytosolic and membrane-bound forms. Moreover, TGase 1 is proteolytically processed, and the major functionally active form consists of a membrane-bound 67/33/10-kDa complex with a myristoylated and palmitoylated amino-terminal 10-kDa membrane anchorage fragment. To understand better how point mutations, deletions, and truncations found in lamellar ichthyosis disease affect the structure and function of TGase 1, we have expressed in baculovirus and keratinocytes a number of reported TGase 1 mutants. The structural implications of these mutations were examined using a homologyderived three-dimensional model of TGase 1 generated from the known x-ray structure of the related coagulation factor XIIIa enzyme. The present studies demonstrate that loss of TGase 1 activity is not restricted to mutations that directly affect the enzymatic activity. We report a new class of mutations that impair the subsequent post-synthetic processing of the protein into its highly active functional forms.

show abstract

“…We and others have shown that mutations in the gene for transglutaminase-1 (TGM1) cause the vast majority of cases of classic LI (Russell et al 1995;Huber et al 1995). An exception is a group of seven families from Northern Africa, where the phenotype co-segregates with markers on chromosome 2, although no gene has yet been identified (Parmentier et al 1996(Parmentier et al , 1999.…”

Section: Introductionmentioning

confidence: 97%

Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies

et al. 2000

View full text Add to dashboard Cite

Lamellar ichthyosis (LI, OMIM no. 242300) is a severe autosomal recessive genodermatosis with an estimated prevalence of 1:200,000. LI represents one end of the spectrum of congenital recessive ichthyosis (CRI). Mutations in the gene for transglutaminase-1 (TGM1) are responsible for many cases of LI and occur throughout the coding sequence of the gene. Our analyses of patients with CRI revealed a common TGM1 mutation involving loss of the intron 5 splice acceptor site leading to alternative splicing of the message. We found families in which the splice acceptor site mutation was homozygous, and families where the patients were compound heterozygotes for the splice acceptor site mutation and another TGM1 mutation. A mutation at this same site occurs in the majority of Norwegian patients as a founder effect. In our ethnically diverse patient population, none of whom have known Norwegian ancestry, haplotype analysis of the TGM1 chromosomal region also suggested the existence of a founder effect. Comparison of the common haplotype in our data with the Norwegian data showed that 2/7 of our splice acceptor site mutation chromosomes had the full reported Norwegian haplotype, and the remaining five chromosomes exhibited recombination at the most distal marker studied. History, family origins, and haplotype analysis suggested that the mutation originally arose on a German background and was introduced into Norway around 800-1000 AD. We also found a limited correlation between genotype and phenotype in our study, with the four homozygous patients having less severe disease than many of the heterozygotes, and no patient with a splice acceptor site mutation having erythroderma or a congenital ichthyosiform erythroderma phenotype.

show abstract

Lamellar Ichthyosis: further narrowing, physical and expression mapping of the chromosome 2 candidate locus

Cited by 32 publications

References 22 publications

Involucrin Cross-linking by Transglutaminase 1

Involucrin Cross-linking by Transglutaminase 1

Transglutaminase 1 Mutations in Lamellar Ichthyosis

Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies

Contact Info

Product

Resources

About