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PubMed2005

Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis.

Harlequin ichthyosis (HI) is the most severe and frequently lethal form of recessive congenital ichthyosis. Although defects in lipid transport, protein phosphatase activity, and differentiation have been described, the genetic basis underlying the clinical and cellular phenotypes of HI has yet to be determined. By use of single-nucleotide-polymorphism chip technology and homozygosity mapping, a common region of homozygosity was observed in five patients with HI in the chromosomal region 2q35. Sequencing of the ABCA12 gene, which maps within the minimal region defined by homozygosity mapping, revealed disease-associated mutations, including large intragenic deletions and frameshift deletions in 11 of the 12 screened individuals with HI. Since HI epidermis displays abnormal lamellar granule formation, ABCA12 may play a critical role in the formation of lamellar granules and the discharge of lipids into the intercellular spaces, which would explain the epidermal barrier defect seen in this disorder. This finding paves the way for early prenatal diagnosis. In addition, functional studies of ABCA12 will lead to a better understanding of epidermal differentiation and barrier formation.

ATP-Binding Cassette Transporters↗
PubMed1997

Transglutaminase 1 mutations in autosomal recessive congenital ichthyosis: private and recurrent mutations in an isolated population.

Autosomal recessive congenital ichthyosis (ARCI) is a rare, heterogenous keratinization disorder of the skin, classically divided into two clinical subtypes, lamellar ichthyosis (LI) and nonbullous congenital ichthyosiformis erythroderma (CIE). Recently, strong evidence for the involvement of the transglutaminase 1 gene (TGM1) in LI has evolved. We have studied ARCI in the isolated Finnish population, in which recessive disorders are often caused by single mutations enriched by a founder effect. Surprisingly, five different mutations of TGM1 (Arg141His, Arg142Cys, Gly217Ser, Val378Leu, and Arg395Leu) were found in Finnish ARCI patients. In addition to affected LI patients, we also identified TGM1 mutations in CIE patients. Moreover, haplotype analysis of the chromosomes carrying the most common mutation, a C-->T transition changing Arg142 to Cys, revealed that the same mutation has been introduced twice in the Finnish population. In addition to this Arg142Cys mutation, three other mutations, in Arg141 and Arg142, have been described elsewhere, in other populations. These findings suggest that this region of TGM1 is more susceptible to mutation. The corresponding amino acid sequence is conserved in other transglutaminases, but, for example, coagulation factor XIII (FXIII) mutations do not cluster in this region. Protein modeling of the Arg142Cys mutation suggested disruption or destabilization of the protein. In transfection studies, the closely related transglutaminase FXIII protein with the corresponding mutation was shown to be susceptible to degradation in COS cells, further supporting evidence of the destabilizing effect of the Arg142Cys mutation in TGM1.

Adolescent↗
PubMed1977

Amnion nodosum and congenital ichthyosis.

Histologic characteristics of the placentas in four cases of amnion nodosum and congenital ichthyosis, a rare association, are presented. Two cases were missed abortions of a single multiparous woman, supporting the hypothesis that in congenital ichthyosis amnion and skin share an abnormal genetic trait. As the amnion showed no hyperkeratosis, it is likely that the amniotic lesions are related to an increased deposition of keratotic plugs on the amnion. Oligohydramnios was verified in two cases; urinary tract malformations were absent in all. The histologic characteristics of the placentas were similar. Noteworthy was the aspect of the chorionic vessels, whose lumens were reduced or obliterated. Perhaps this feature contributed to the poor nutrition of the amnion, a fact assumed by some authors to explain lesions of amnion nodosum. As these vascular alterations are common after fetal death, it is only in the placenta of the newborn that the vascular changes, compatible with rubella vasculitis, may have altered the nutrition of the amnion.

Amnion↗
PubMed1995

Autosomal recessive lamellar ichthyosis: identification of a new mutation in transglutaminase 1 and evidence for genetic heterogeneity.

Autosomal recessive lamellar ichthyosis (ARLI) belongs to the group of congenital disorders of cornification. It is characterized by a severe and generalized ichthyosis, and other variable cutaneous signs. The human transglutaminase 1 (TGM1) gene was recently found to be the disease-causing gene. Linkage analysis in 23 families (of which 13 were consanguineous) showed that for 10 of them, the disease was linked to the TGM1 gene. A new deleterious mutation introducing a stop codon in the TGM1 reading frame was found. Nevertheless, for the 13 other ARLI families, TGM1 was found to be unlinked to the disease. The present data show that ARLI is genetically heterogeneous and confirm that TGM1 is one of the responsible genes.

Base Sequence↗
PubMed2004

Mutations in ichthyin a new gene on chromosome 5q33 in a new form of autosomal recessive congenital ichthyosis.

We report the genomic localization by homozygosity mapping and the identification of a gene for a new form of non-syndromic autosomal recessive congenital ichthyosis. The phenotype usually presents as non-bullous congenital ichthyosiform erythroderma with fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. A few patients presented a more generalized lamellar ichthyosis. Palmoplantar keratoderma was present in all cases, whereas only 60% of the patients were born as collodion babies. Six homozygous mutations including one nonsense and five missense mutations were identified in a new gene, ichthyin, on chromosome 5q33 in 23 patients from 14 consanguineous families from Algeria, Colombia, Syria and Turkey. Ichthyin encodes a protein with several transmembrane domains which belongs to a new family of proteins of unknown function localized in the plasma membrane (PFAM: DUF803), with homologies to both transporters and G-protein coupled receptors. This family includes NIPA1, in which a mutation was recently described in a dominant form of spastic paraplegia (SPG6). We propose that ichthyin and NIPA1 are membrane receptors for ligands (trioxilins A3 and B3) from the hepoxilin pathway.

Amino Acid Sequence↗
PubMed2004

Lethal, neonatal ichthyosis with increased proteolytic processing of filaggrin in a mouse model of Netherton syndrome.

Netherton syndrome is an autosomal recessive multisystemic disorder characterized by congenital ichthyosiform erythroderma, hair shaft defects and atopy, caused by mutations within the human SPINK5 gene. To investigate the development of this disease, we have cloned mouse spink5 and created mice with a mutated premature stop codon at amino acid R820X, to produce an allele that closely mimics a point mutation (E827X) in human SPINK5. Newborn spink5(R820X/R820X) mice develop a lethal, severe ichthyosis with a loss of skin barrier function and dehydration, resulting in death within a few hours of birth, similar to that observed in patients with severe Netherton syndrome. Epidermal barrier function is compromised because of the stratum corneum becoming spontaneously detached in the newborn mice, and this is probably compounded by the reduced mechanical strength detected in the cornified envelopes. Biochemical analysis of skin from newborn wild-type and spink5(R820X/R820X) mice revealed a substantial increase in the proteolytic processing of profilaggrin into its constituent filaggrin monomers. Filaggrin functions to organize keratin filaments into highly ordered macrofibrils that crisscross the cornified cells of the stratum corneum imparting structural integrity, and defects in filaggrin processing occur in a number of forms of congenital ichthyosis. These data suggest that in the absence of the serine protease inhibitor spink5, there is an abnormal increase in the processing of profilaggrin, resulting in an overabundance of filaggrin monomers, and that this may play a direct role in the observed deficit in the adhesion of the stratum corneum and the severely compromised epidermal barrier function.

Amino Acid Sequence↗
PubMed2006

Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature-sensitive phenotype.

Bathing suit ichthyosis (BSI) is a striking and unique clinical form of autosomal recessive congenital ichthyosis characterized by pronounced scaling on the bathing suit areas but sparing of the extremities and the central face. Here we report on a series of 10 BSI patients. Our genetic, ultrastructural and biochemical investigations show that BSI is caused by transglutaminase-1 (TGase-1) deficiency. Altogether, we identified 13 mutations in TGM1-among them seven novel missense mutations and one novel nonsense mutation. Structural modeling for the Tyr276Asn mutation reveals that the residue is buried in the hydrophobic interior of the enzyme and that the hydroxyl side chain of Tyr276 is exposed to solvent in a cavity of the enzyme. Cryosections of healthy skin areas demonstrated an almost normal TGase activity, in contrast to the affected BSI skin, which only showed a cytoplasmic and clearly reduced TGase-1 activity. The distribution of TGase-1 substrates in the epidermis of affected skin corresponded to the situation in TGase-1 deficiency. Interestingly, the expression of TGase-3 and cathepsin D was reduced. Digital thermography validated a striking correlation between warmer body areas and presence of scaling in patients suggesting a decisive influence of the skin temperature. In situ TGase testing in skin of BSI patients demonstrated a marked decrease of enzyme activity when the temperature was increased from 25 to 37 degrees C. We conclude that BSI is caused by TGase-1 deficiency and suggest that it is a temperature-sensitive phenotype.

Adolescent↗
PubMed1987

Deletion of a DNA sequence in eight of nine families with X-linked ichthyosis (steroid sulphatase deficiency).

Deficiency of steroid sulphatase (STS) is associated with ichthyosis, with failure of the placental production of oestriol in late pregnancy and with difficulties in childbirth. The STS gene has been localised by deletion mapping to the distal tip of the snort arm of the X chromosome, and is of interest in that it appears to escape X-inactivation. We have constructed an X-specific DNA library and screened it for single copy DNA sequences which lie at the distal end of Xp. The sequence GMGX9 was found to map in the interval Xp22.3-pter and to detect a frequent HindIII polymorphism. We have used GMGX9 in linkage studies in families with classical X-linked ichthyosis and this has not only shown tight linkage with STS deficiency but has also revealed that the sequence is deleted in affected males in eight of nine families. GMGX9 is present in all of 26 normal male individuals so far examined. Our findings suggest that a high proportion of the mutations at the STS locus leading to enzyme deficiency are deletions, presumably generated by unequal cross-over events in female meiosis or by illegitimate X-Y interchange in male meiosis.

Base Sequence↗
PubMed2004

Nutritional status and gastrointestinal structure and function in children with ichthyosis and growth failure.

UNLABELLED: Growth failure occurs in several of the ichthyoses, a heterogeneous group of inherited disorders characterized by thickened or scaly skin. This suggests that there may be common pathogenic mechanisms causing failure to thrive. Previous studies have proposed that a hypermetabolic state induced by epidermal inflammation and hyperproliferation or enteropathy leading to malabsorption and nutritional deficiencies might account for the growth failure in icthyosis. OBJECTIVE: The purpose of this study was to examine the extent of enteropathy and nutritional deficiency in children with severe ichthyosis and growth failure. METHODS: Ten children with different types of ichthyoses and growth failure were studied. RESULTS: Evaluation of gastrointestinal structure and function revealed few abnormalities other than mild fat malabsorption in two patients. Total caloric intake exceeded established requirements for age, height, and weight in all patients. Deficiencies of fat-soluble vitamins were identified in a few subjects. Mild elevations in total calcium and magnesium blood level, elevated hematocrit levels, and constipation were observed in many patients. CONCLUSIONS: Nutritional deficiencies and gastrointestinal abnormalities are uncommon in children with ichthyosis and failure to thrive. Chronic hypovolemia caused by impaired epidermal permeability barrier may be common in this population.

Calcium↗
PubMed2026

X-linked ichthyosis with seizures, ADHD, and autism spectrum disorder: a case report with an uncommon clinical presentation.

INTRODUCTION AND IMPORTANCE: X-linked ichthyosis (XLI) is a genetic condition characterized by scaly skin due to steroid sulfatase (STS) deficiency, often associated with additional neurodevelopmental issues. CASE PRESENTATION: A 10-year-old male child was admitted to the dermatology department. The child had been born prematurely at 26 weeks' gestation with a low birth weight of 1.6 kg. He presented with seizures characterized by abnormal upper-limb movements and was diagnosed with congenital ichthyosis. The child exhibited delayed language and motor development, learning difficulties, microcephaly, and dry, scaly skin, which he habitually peeled and ingested. Genetic analysis (single-nucleotide polymorphism and combined comparative genomic hybridization) revealed a 1.65 Mb deletion on chromosome Xp22.31 affecting the STS gene and other adjacent genes. The patient had low STS enzyme activity (3.5 nmol/hour/protein) in adipose tissue. Neuroimaging showed no structural abnormalities, though an electroencephalogram indicated mild slowing. CLINICAL DISCUSSION: Given the established association between STS deletions and neurodevelopmental as well as psychiatric comorbidities, early recognition of emerging psychiatric features is essential. Given the established association between STS deletions and neurodevelopmental as well as psychiatric comorbidities, early recognition of emerging psychiatric manifestations is essential. Management should follow evidence-based recommendations for first-episode or early psychotic symptoms, emphasizing careful assessment, individualized pharmacological treatment when indicated, and multidisciplinary psychosocial support. Such an approach may improve clinical stabilization while avoiding premature diagnostic labeling. CONCLUSION: This case highlights the importance of early genetic diagnosis and personalized treatment approaches, integrating dermatological, neurological, and psychiatric care to optimize outcomes in XLI.

X-linked ichthyosis↗
PubMed1997

Harlequin ichthyosis keratinocytes in lifted culture differentiate poorly by morphologic and biochemical criteria.

Harlequin ichthyosis (HI) is a severe congenital ichthyosis in which massively thickened stratum corneum with abnormal barrier function often results in death of affected newborns. Survivors evolve into a severe nonbullous ichthyosiform erythroderma. Previously we have ascertained three biochemical phenotypes of HI, based on abnormal profilaggrin and K6 and K16 expression in epidermis. Submerged cultures of HI keratinocytes differentiated abnormally, but the three phenotypes were indistinguishable in vitro. We hypothesized that differentiation in submerged culture was insufficient to reflect in vivo biochemical abnormalities or that dermal components might be necessary for expression. To test these hypotheses HI keratinocytes and fibroblasts (n = 3) were grown on collagen gels at the air-medium interface in a cross-over design with normal keratinocytes and fibroblasts. Epithelia derived from lifted cultures were studied by light microscopy and immunocytochemistry and extracted for western blot analysis. In contrast to our prediction, lifted cultures of HI keratinocytes formed a poorly differentiated epithelium, and normal keratinocytes formed an epidermal-like tissue with expression of K1 and expression and processing of profilaggrin to filaggrin. In addition, the presence of HI fibroblasts consistently altered differentiation of both HI and normal keratinocytes, resulting in less complete morphologic differentiation. The findings suggest that both epithelial and mesenchymal elements of the skin from HI are affected but that the primary abnormality lies in the keratinocytes.

Adult↗
PubMed1995

Reduced skin barrier function parallels abnormal stratum corneum lipid organization in patients with lamellar ichthyosis.

Most patients with autosomal recessive lamellar ichthyosis are known to have markedly impaired skin barrier function. We hypothesize that this may be due to imperfections in the composition and fine structure of the intercellular stratum corneum lipids. The aim of the present study was to test this hypothesis. To characterize the barrier properties in three female patients with lamellar ichthyosis, the following parameters were used and compared with those of healthy volunteers: transepidermal water loss, stratum corneum lipid profiles after topical acetone/ether extraction on the flexure side of the forearm, and small-angle x-ray diffraction. The extracted lipids were separated using high performance thin-layer chromatography and quantified, and the ceramide profile was determined. Small-angle x-ray diffraction was used to obtain information on the molecular structure and organization of the intercellular lipid domains of stratum corneum using stratum corneum scales collected by scraping. Transepidermal water loss was significantly increased in all three patients. Lipid analysis showed significant differences in the relative amounts of ceramide fractions 2-3a-3b-4-5, free fatty acid-ceramide ratio, and free fatty acid-cholesterol ratio. Small-angle x-ray diffraction showed smaller repeated distances of lipid bilayers in stratum corneum samples of the patients compared with the healthy volunteers. An additional diffraction peak was found in the patients compared with the healthy volunteers, which can be ascribed to crystalline cholesterol. These data suggest that there might be a relation between the impaired barrier function and stratum corneum lipid structural and composition changes.

Adult↗
PubMed1984

Lipids in the pathogenesis of ichthyosis: topical cholesterol sulfate-induced scaling in hairless mice.

Although several abnormalities of lipid metabolism have been associated with abnormal cornification in humans, evidence that these lipids directly provoke abnormal scale is lacking. One recently described example of a lipid abnormality in ichthyosis is absence of the enzyme steroid sulfatase in recessive X-linked ichthyosis (RXLI). This enzyme normally desulfates cholesterol sulfate (CS) and sulfated steroid hormones, including dehydroepiandrosterone sulfate (DHEAS). As a result of this enzyme deficiency, patients with RXLI accumulate CS in their blood and skin. To determine whether sulfated sterols are the specific cause of increased scale, we applied CS, DHEAS, cholesterol, or vehicle alone to the backs of hairless mice. In animals treated with CS, but not with DHEAS or with vehicle, visible scale without erythema appeared after 1 week, peaked at 2 weeks, and then diminished. When the dose of CS was doubled, abnormal scale reappeared and then decreased again. CS-induced scale was reversible, clearing within 3 days of discontinuation of treatment. Because there was no acanthosis, dermal inflammation, abnormal transepidermal water loss, or increased labeling index, it appears that the 3-fold increase in thickness of the stratum corneum in CS-treated animals is due to a direct effect on this layer.

Animals↗
PubMed1994

Ichthyosis bullosa of Siemens--a disease involving keratin 2e.

Ichthyosis bullosa of Siemens (IBS) is a congenital bullous ichthyosis without erythroderma. In contrast to bullous congenital ichthyosiform erythroderma (BCIE), there is a relatively mild involvement of the skin and epidermolytic hyperkeratosis (EHK) is restricted to the upper suprabasal layers of the epidermis. Tonofilament aggregation was observed by EM in suprabasal cells from affected patients in the two families under study, indicative of a keratin abnormality. Keratin 2e is a differentiation specific type II keratin expressed suprabasally in the epidermis. Part of the K2e gene was amplified by polymerase chain reaction using genomic DNA from affected and unaffected individuals from two IBS families. Direct sequencing of polymerase chain reaction products revealed a point mutation in the highly conserved helix termination motif, producing the protein sequence change LLEGEE-LLEGKE. This mutation was found in all affected members of a five-generation kindred and also in a sporadic case in a second unrelated family. No mutation was seen in unaffected individuals. The mutation destroys a MnlI restriction site, which allowed exclusion of the mutation from a population of 50 unaffected unrelated individuals by restriction fragment analysis of K2e PCR products. This is the sixth keratin gene found to be involved in an inherited epidermal disorder.

Base Sequence↗
PubMed1987

Keratinocytes cultured from subjects with ichthyosis vulgaris are phenotypically abnormal.

Ichthyosis vulgaris (IV) is an autosomal dominant, scaling disorder in which keratohyaline granules and filaggrin are reduced in or absent from the epidermis of affected individuals. Morphologic and biochemical markers of epidermal differentiation were studied in keratinocytes cultured from clinically unaffected skin of patients with IV, from clinically unaffected skin of an obligate gene carrier, and from normal skin of unaffected family members and an adult volunteer. Cultured keratinocytes from affected subjects formed thickened layers of scaly cells that failed to react with monoclonal antibody to filaggrin. In contrast, normal cells contained many large, immunoreactive granules. Electron microscopy confirmed the absence of keratohyaline granules in affected cells and the presence of large keratohyaline granules in normal cells. Immunoblot analysis of keratinocyte extracts from subjects with ichthyosis showed that profilaggrin was absent, but no differences in keratins were detected between affected and control cells. For all parameters, findings in cells of the clinically unaffected obligate gene carrier were intermediate between those from affected patients and controls. We conclude that keratinocytes cultured from patients with IV maintain structural and biochemical phenotypic characteristics of the disease in vitro.

Biopsy↗
PubMed1988

Calorimetric and electron spin resonance examination of lipid phase transitions in human stratum corneum: molecular basis for normal cohesion and abnormal desquamation in recessive X-linked ichthyosis.

Lipids appear to play a critical role as regulators of stratum corneum desquamation. In this study, we observed discrete lipid phase transitions at physiologic temperatures in both normal human scale (NHS) and in lipid extracts of NHS by differential scanning calorimetry. In contrast, such thermal transitions were not observed in recessive x-linked ichthyosis scale (RXLIS). To gain further insight into the molecular basis of the lipid phase transitions in NHS vs. RXLIS, comparable samples were evaluated by electron spin resonance, utilizing the perdeuterated probe, di-t-butyl nitroxide. Upon electron spin resonance analysis, both NHS and RXLIS demonstrated thermal phase transitions in the physiologic range; however, the nature of the lipid environments in each type varied. Whereas the environment of the spin probe was more polar in NHS than in RXLIS, the spin probe partitioned into a more "fluid" environment in RXLIS; i.e., the spin probe was more mobile in RXLIS than in NHS lipid matrices. Because an alteration in the cholesteryl sulfate:cholesterol ratio is the primary lipid abnormality in RXLIS, model cholesterol-fatty acid-cholesteryl sulfate mixtures were prepared in proportion to the lipid composition of NHS and RXLIS. Differences were observed in both thermal transitions and in lipid microenvironments in these mixtures that paralleled those observed in scale samples. Based on these results, a model is proposed that invokes abnormal hydrogen bonding, due to increased cholesteryl sulfate, as the mechanism for the abnormal desquamation in recessive X-linked ichthyosis.

Butanes↗
PubMed1992

Abnormal lamellar granules in harlequin ichthyosis.

Lamellar granules are specialized lipid-rich organelles present in epidermal granular cells. They fuse with the apical cell surface and discharge their contents into the intercellular space forming lamellar sheets. It was previously shown by electron microscopy that lamellar granules in biopsies of infants affected with harlequin ichthyosis are either absent or abnormal and no intercellular lamellae could be detected. A monoclonal antibody (AE17) directed against a protein component of lamellar granules was used for immunoblotting and immunohistochemical studies as an indication of both the presence and function of lamellar granules. Epidermal extracts from all harlequin and normal specimens tested showed an immunoreactive protein of 25-28 kD. Immunohistochemical staining of normal skin using AE17 showed apical cytoplasmic staining in the granular layer and intercellular staining between the granular and stratum corneum cells. Harlequin samples showed variable degrees of staining ranging from little to heavy apical cytoplasmic staining of granular cells. No intercellular staining was detected. The immunohistochemical staining pattern correlated with the electron microscopic localization of abnormal vesicles and the absence of intercellular lamellae in the affected samples. We conclude that the vesicles represent lamellar granules that contain the AE17 antigen but are structurally abnormal and defective in their ability to discharge both their lipid and protein contents into the intercellular space. We suggest that this defect in the lamellar granules represents the underlying basis for stratum corneum cell retention and subsequent accumulation of scale in harlequin ichthyosis.

Adult↗
PubMed1990

Heterogeneity in harlequin ichthyosis, an inborn error of epidermal keratinization: variable morphology and structural protein expression and a defect in lamellar granules.

Skin biopsies and scale samples from nine infants and one fetus affected with harlequin ichthyosis (HI) were obtained from eight families. Epidermal differentiation was examined by morphologic and biochemical criteria and cell culture studies. Two striking abnormalities were identified; first, keratin and filaggrin expression were abnormal and varied between cases, and, second, in all cases lamellar granules were absent or abnormal, and intercellular lamellae within the stratum corneum were absent. Three HI phenotypes were distinguished by variable expression of epidermal structural proteins. Cases were classified by the absence (type 1) or presence (types 2 and 3) of keratins K6 and K16 ("hyperproliferative" keratins) and by the presence of profilaggrin in the interfollicular epidermis (types 1 and 2 only). Profilaggrin is apparently not converted to filaggrin, but it is retained in the scale. The block in profilaggrin processing may be due to an inactive phosphatase. Siblings in two families (presenting with types 1 and 2) showed the same type classification suggesting that expression of the phenotype is consistent within families but differs between families. Cultured HI keratinocytes were normal by phase microscopy, but abnormal by electron microscopy with no lamellar granules and extensive stacking of the upper layers. We conclude that harlequin ichthyosis is a genetically heterogeneous group of disorders with altered lamellar granules, intercellular lipids, and variation in expression and/or processing of structural protein markers of normal epidermal keratinization. Furthermore, the lamellar granule and structural protein defects may be indirectly related via a mechanism involving phosphorylation/dephosphorylation.

Biopsy↗