Clinical and morphological correlations for transglutaminase 1 gene mutations in autosomal recessive congenital ichthyosis.
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Autosomal recessive congenital ichthyosis (ARCI) is a group of inherited disorders of cornification in which progress has recently been made in the identification of pathogenic mechanisms causing the disease. Transglutaminase 1 (TGM1) has been found as a defective gene in a large fraction of patients with lamellar ichthyosis (LI), a severe inherited scaling disorder of the skin. We have previously performed molecular genetic studies of 38Finnish ARCI families and found six different mutations in 13 families of 38 (34%). In this study we compared the molecular genetic alterations with clinical and electron microscopic findings of these patients. Families were classified by electron microscopy in ichthyosis congenita (IC) types I, II, III, IV and a non-defined group. TGM 1 gene mutation was found in all of the IC type II and 1/3 of the IC type 1 families. Although electron microscopy is not always used to classify ARCI patients, it can distinguish groups which are parallel with molecular genetic findings. This finding might be useful in the classification of ARCI patients for further linkage studies. Clinically typical phenotype of the TGM1 mutation carrier includes large, thick, brownish scales, but ichthyosis of some of these patients tends to be milder. (+info)
Two new loci for autosomal recessive ichthyosis on chromosomes 3p21 and 19p12-q12 and evidence for further genetic heterogeneity.
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Autosomal recessive ichthyosis (ARI) includes a heterogeneous group of disorders of keratinization characterized by desquamation over the whole body. Two forms largely limited to the skin have been defined: lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE). A first gene for LI, transglutaminase TGM1, has been identified on chromosome 14, and a second one has been localized on chromosome 2. In a genomewide scan of nine large consanguineous families, using homozygosity mapping, two new loci for ARI were found, one for a lamellar form in a 6-cM interval on chromosome 19 and a second for an erythrodermic form in a 7.7-cM interval on chromosome 3. Linkage to one of the four loci could be demonstrated in more than half of 51 consanguineous families, most of them from the Mediterranean basin. All four loci could be excluded in the others, implying further genetic heterogeneity in this disorder. Multipoint linkage analysis gave maximal LOD scores of 11.25 at locus D19S566 and 8.53 at locus D3S3564. (+info)
The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis.
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The Comel-Netherton syndrome is an autosomal recessive multisystemic disorder characterized by localized or generalized congenital ichthyosis, hair shaft abnormalities, immune deficiency, and markedly elevated IgE levels. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and failure to thrive. To study the clinical presentations of the Comel-Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of various ethnic backgrounds. Results of initial linkage studies mapped the Comel-Netherton syndrome in 12 multiplex families to a 12 cM interval on 5q32, thus confirming genetic homogeneity of Comel-Netherton syndrome across families of different origins. The Comel-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in epithelial and lymphoid tissues. Recently, recessive mutations in SPINK5 were identified in several Comel-Netherton syndrome patients from consanguineous families. We used heteroduplex analysis followed by direct DNA sequencing to screen all 33 exons and flanking intronic sequences of SPINK5 in the affected individuals of our cohort. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 Comel-Netherton syndrome families. The nucleotide changes included four non-sense mutations, eight small deletions or insertions leading to frameshift, and five splice site defects, all of which are expected to result in premature terminated or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including two recurrent mutations. Genotype-phenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKT1 are associated with a severe phenotype. For the first time, we used molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comel-Netherton syndrome. (+info)
Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1.
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We report the identification of mutations in lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) genes in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17. Linkage disequilibrium analysis of six families affected by NCIE permitted us to reduce a recently reported interval of 8.4 cM on chromosome 17p13.1 to a 600 kb region around the marker D17S1796, which contains LOX genes. LOX products have long been implicated in skin disorders. Two point mutations and one deletion were found in ALOXE3 and three point mutations were found in ALOX12B in these consanguineous families from the Mediterranean basin. ALOXE3 and ALOX12B are two genes which are physically linked and functionally related. They are separated by 38 kb, have one more exon than the other LOX genes and are mainly expressed in epithelial cells including keratinocytes. Although the main substrate(s) of the two enzymes is (are) still unknown, the products of ALOX12B obtained in experimental systems have been demonstrated to be of R-chirality. It seems likely that the product of one of these enzymes may be the substrate of the other, and that they belong to the same metabolic pathway. (+info)
Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families.
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Netherton syndrome is a severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Recently, we identified SPINK5, which encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), as the defective gene in Netherton syndrome. Here we describe the intron-exon organization of the gene and characterize the SPINK5 mutations in patients from 21 families of different geographic origin, using denaturing high performance liquid chromatography and direct sequencing. We identified 18 mutations, of which 13 were novel and seven (39%) were recurrent. The majority of the mutations were clustered between exons 1-8 and exons 21-26. They comprised four nonsense mutations (22%), eight frameshift insertions or deletions (44%), and six splice-site defects (33%). All mutations predict the formation of premature termination codons. Northern blot analysis showed variable reduction of SPINK5 mutant transcript levels, suggesting variable efficiency of nonsense-mediated mRNA decay. Seven patients were homozygotes, eight were compound heterozygotes, and five were heterozygotes with only one identifiable SPINK5 mutation. Five mutations, one of which resulted in perinatal lethal disease in three families, were associated with certain ethnic groups. We also describe 45 intragenic polymorphisms in the patients studied. The clinical features of erythroderma, trichorrhexis invaginata, and atopic manifestations were present in the majority of affected individuals and ichthyosis linearis circumflexa was seen in 12 out of 24 patients. Interfamilial and intrafamilial variation in disease severity was observed, with no clear correlation between mutations and phenotype, suggesting that the degree of severity may be affected by other factors. (+info)
LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome.
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SPINK5, encoding the putative multi-domain serine protease inhibitor LEKTI, was recently identified as the defective gene in the severe autosomal recessive ichthyosiform skin condition, Netherton syndrome (NS). Using monoclonal and polyclonal antibodies, we show that LEKTI is a marker of epithelial differentiation, strongly expressed in the granular and uppermost spinous layers of the epidermis, and in differentiated layers of stratified epithelia. LEKTI expression was also demonstrated in normal differentiated human primary keratinocytes (HK) through detection of a 145 kDa full-length protein and a shorter isoform of 125 kDa. Both proteins are N-glycosylated and rapidly processed in a post-endoplasmic reticulum compartment into at least three C-terminal fragments of 42, 65 and 68 kDa, also identified in conditioned media. Processing of the 145 and 125 kDa precursors was prevented in HK by treatment with a furin inhibitor. In addition, in vitro cleavage of the recombinant 145 kDa precursor by furin generated C-terminal fragments of 65 and 68 kDa, further supporting the involvement of furin in LEKTI processing. In contrast, LEKTI precursors and proteolytic fragments were not detected in differentiated HK from NS patients. Defective expression of LEKTI in skin sections was a constant feature in NS patients, whilst an extended reactivity pattern was observed in samples from other keratinizing disorders, demonstrating that loss of LEKTI expression in the epidermis is a diagnostic feature of NS. The identification of novel processed forms of LEKTI provides the basis for future functional and structural studies of fragments with physiological relevance. (+info)
Transgenic mice expressing a mutant keratin 10 gene reveal the likely genetic basis for epidermolytic hyperkeratosis.
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Epidermolytic hyperkeratosis (EH; previously called bullous congenital ichthyosiform erythroderma) is an autosomal dominant skin disease of unknown etiology, affecting approximately 1 out of 300,000 people. It is typified by hyperkeratotic scaliness, blistering due to cytolysis within suprabasal epidermal cells, and hyperproliferation in basal cells. Histologically, EH epidermis exhibits a thickened stratum corneum and granular layer, with enlarged and irregular-shaped cells. Ultrastructurally, only suprabasal layers are affected, with three major aberrancies: (i) tonofilament clumping, (ii) nuclei and keratohyalin granules of irregular shape and size, and (iii) cell degeneration. We have discovered that transgenic mice expressing a mutant keratin 10 gene have the EH phenotype, thereby suggesting that a genetic basis for human EH residues in mutations in genes encoding suprabasal keratins K1 and K10. In addition, we show that (i) stimulation of basal cell proliferation can arise from a defect in suprabasal cells, and (ii) distortion of nuclear shape or aberrations in cytokinesis can occur when an intermediate filament network is perturbed. (+info)
SPINK5 and Netherton syndrome: novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases.
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Netherton syndrome (NTS) is an autosomal recessive congenital ichthyosis featuring chronic inflammation of the skin, hair anomalies, epidermal hyperplasia with an impaired epidermal barrier function, failure to thrive and atopic manifestations. The disease is caused by mutations in the SPINK5 gene encoding the serine proteinase inhibitor lympho-epithelial Kazal-type inhibitor (LEKTI). Sequence analyses of SPINK5 in seven NTS patients from five different families allowed us to identify two known and three novel mutations all creating premature termination codons. We developed a monoclonal antibody giving a strong signal for LEKTI in the stratum granulosum of normal skin and demonstrated absence of the protein in NTS epidermis. Immunoblot analysis revealed presence of full length LEKTI and of LEKTI cleavage fragments in normal hair roots, whereas in NTS hair roots LEKTI and its cleavage products were completely missing. Transglutaminase1 activity was present throughout almost the entire suprabasal epidermis in NTS, whereas in normal skin it is restricted to the stratum granulosum. In contrast, immunostaining for transglutaminase3 was absent or faint. Moreover, comparable with the altered pattern in psoriatic skin the epidermis in NTS strongly expressed the serine proteinase inhibitor SKALP/elafin and the anti-microbial protein human beta-defensin 2. These studies demonstrate LEKTI deficiency in the epidermis and in hair roots at the protein level and an aberrant expression of other proteins, especially transglutaminase1 and 3, which may account for the impaired epidermal barrier in NTS. (+info)