Mutation In Loricrin Research Articles

Early diagnosis of Voh Winkel syndrome-inherited honeycombed hands and hearing loss

Voh-Winkel Syndrome with approximately 50 cases reported in literature is a rare inherited Palmoplantar keratoderma characterised by honeycomb like hyperkeratosis, hearing loss or ichthyosis. It also features constricting fibrous bands that develop at the base of fingers/toes and later get strangulated to cause autoamputation called pseudoainhum. It is an autosomal dominant disorder with mutations in loricrin and connexin genes leading to hearing loss and ichthyosis variants respectively and manifests in infancy and becomes apparent later in childhood or adult life. Early diagnosis of this condition and management by multiple specialities given the associated features therefore becomes an absolute necessity. An emphasis on dermatological examination to manage hyperkeratosis using topical and systemic therapy, otorhinolaryngology to manage hearing loss as well as plastic surgery to alleviate symptoms arising due to the constriction bands is mandatory for effective management of this condition. Here we report a 22-year-old female patient who came with Palmoplantar keratoderma, bilateral hearing loss and pseudo-ainhum.

A rare case of Vohwinkel’s syndrome

Keratoderma hereditarium mutilans or Vohwinkel’s syndrome is a rare autosomal dominant type of palmoplantar keratoderma characterized by honeycomb appearance, pseudoainhum leading to auto-amputation and stellate keratosis on knuckles. It’s mode of inheritance is autosomal dominant with mutation in loricrin and connexin 26 genes. We report the case of a 35-year-old female with alopecia universalis since birth and transgradient palmoplantar keratoderma, impaired hearing and pseudoainhum formation since childhood. This case is being reported to highlight the association of Vohwinkel’s syndrome with sensorineural hearing loss and alopecia universalis.

Loricrin downregulation and epithelial-related disorders: a systematic review.

Loricrin downregulation has been associated with age-related changes as well as inherited and inflammatory skin diseases. We hypothesize that changes in loricrin could be more related to altered barrier function and consequently disorders that affect epithelial cells, such as psoriasis, atopic dermatitis (AD), erythrokeratoderma, loricrin keratoderma (LK) and periodontitis. The aim of this review is to summarize what is known about the association between loricrin downregulation and epithelial-related disorders (ERDs). A search was performed on the following databases: Medline, Cochrane Library, PubMed, EMBASE, Lilacs, Scopus and Google Scholar, resulting in 16 included articles. Loricrin keratoderma was the ERD most frequently associated with loricrin mutations (730insG, 709insC and 578insG; 5/7 cases - 71.44%). Atopic dermatitis was the ERD most frequently associated with loricrin downregulation (2/7 cases - 28.6%). Mutilating palmoplantar keratoderma, progressive symmetrical erythrokeratoderma and a new type of erythrokeratoderma were not associated with any mutations. At the gene level, periodontitis patients showed the highest decrease (-6.89x), followed by AD (-6.5x) and psoriasis patients (-0.5x). In summary, loricrin mutation and downregulation were associated with several ERDs. The diversity in disease presentation is likely related to whether there is a total loss of loricrin, mislocalization and/or if the mutant form of loricrin causes dysfunction of other proteins and/or changes in cornification.

Vohwinkel syndrome, ichthyosiform variant - by Camisa - Case report

Vohwinkel syndrome or keratoderma hereditaria mutilans is a rare autosomal dominant palmoplantar keratosis, which manifests in infants and becomes more evident in adulthood. Its mode of inheritance is autosomal dominant with mutation in loricrin and Connexin 26 genes. Patients with this mutation present hyperkeratosis of the palms and soles, constricting bands of the digits, usually on the fifth, and starfish-shaped hyperkeratosis on the dorsal aspects of the hands and feet. The disease mostly occurs in white women, where constricting fibrous bands appear on the digits and can lead to progressive strangulation and auto-amputation (pseudo-ainhum).The authors report a rare case of a patient with a clinical ichthyosiform variant of Vohwinkel syndrome.

A new variant of Vohwinkel syndrome: A case report

Vohwinkel syndrome (mutilating and diffuse palmoplantar keratoderma) is associated with various extracutaneous features including icthyosis and deafness. Its mode of inheritance is autosomal dominant with mutation in loricrin and Connexin 26 genes. Here we report a mutilating and focal palmoplantar keratoderma in two siblings with congenital hypotrichosis and probably autosomal recessive inheritance that appears to be a new variant of Vohwinkel syndrome.

A novel c.545-546insG mutation in the loricrin gene correlates with a heterogeneous phenotype of loricrin keratoderma

Loricrin keratoderma (LK) is a group of congenital skin abnormalities characterized by the common features of honeycomb palmoplantar keratoderma and diffused ichthyosiform dermatosis. Earlier studies have shown that LK is associated with genetic defects of the loricrin gene. To determine the correlation between a loricrin mutation and a heterogeneous phenotype of loricrin keratoderma. We obtained DNA samples from a large family in which affected members showed more severe hyperkeratosis on the dorsal parts of their hands, mild palmoplantar keratoderma with no honeycomb-like manifestations and generalized ichthyosis. Screening of the loricrin gene was performed by direct sequencing of the entire coding region. Plasmids encoding the green fluorescent protein-tagged human loricrin were constructed and transferred to 293A cells for subcellular localization analyses. Molecular analyses of the loricrin gene identified a novel insertion mutation c.545-546insG that resulted in a frameshift after codon 182. This mutation was predicted to produce a mutant protein with a frameshift of its C-terminal sequence of amino acids that embeds a newly generated nuclear localization signal (NLS), and to be 22 amino acids longer than the wild-type protein due to a delayed termination codon. The NLSs appear to result in an accumulation of mutant loricrin within nuclei. Our results extend the repertoire of loricrin mutations underlying LK, provide further evidence that heterogeneous phenotypes of LK may be the result of genetic heterogeneity of loricrin mutations, and demonstrate that nuclear accumulation of mutant loricrin is due to the nuclear targeting sequences in the mutant C-terminus.

Thematic review series: Skin Lipids. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism

Many of the ichthyoses are associated with inherited disorders of lipid metabolism. These disorders have provided unique models to dissect physiologic processes in normal epidermis and the pathophysiology of more common scaling conditions. In most of these disorders, a permeability barrier abnormality "drives" pathophysiology through stimulation of epidermal hyperplasia. Among primary abnormalities of nonpolar lipid metabolism, triglyceride accumulation in neutral lipid storage disease as a result of a lipase mutation provokes a barrier abnormality via lamellar/nonlamellar phase separation within the extracellular matrix of the stratum corneum (SC). Similar mechanisms account for the barrier abnormalities (and subsequent ichthyosis) in inherited disorders of polar lipid metabolism. For example, in recessive X-linked ichthyosis (RXLI), cholesterol sulfate (CSO(4)) accumulation also produces a permeability barrier defect through lamellar/nonlamellar phase separation. However, in RXLI, the desquamation abnormality is in part attributable to the plurifunctional roles of CSO(4) as a regulator of both epidermal differentiation and corneodesmosome degradation. Phase separation also occurs in type II Gaucher disease (GD; from accumulation of glucosylceramides as a result of to beta-glucocerebrosidase deficiency). Finally, failure to assemble both lipids and desquamatory enzymes into nascent epidermal lamellar bodies (LBs) accounts for both the permeability barrier and desquamation abnormalities in Harlequin ichthyosis (HI). The barrier abnormality provokes the clinical phenotype in these disorders not only by stimulating epidermal proliferation, but also by inducing inflammation.

Variant of Vohwinkel′s syndrome

A 28-year-old female born to consanguineous parents, presented with progressive palmoplantar keratoderma since the age of six months and a constricting band on right fourth finger of one year duration. There was history of similar complaints being present in two other family members. Associated clinical findings included starfish-shaped cornified plaques on knuckles, resorption of distal phalanges and keratotic plaques on elbows, groins and knees. The patient was mentally sound and had normal audiometry. Biopsy from hyperkeratotic plaque showed hyperkeratosis, parakeratosis, increased granular layer and papillomatosis. Gene mapping for loricrin mutation was found to be negative.

Towards characterization of palmoplantar keratoderma caused by gain-of-function mutation in loricrin: analysis of a family and review of the literature

Loricrin keratoderma is an autosomal dominant palmoplantar keratoderma heterogeneous in clinical appearance. We report a family with diffuse ichthyosis and honeycomb palmoplantar keratoderma but no occurrence of pseudoainhums or autoamputations. All patients were born as collodion babies and displayed prominent knuckle pads. We identified the previously reported mutation 730insG in LOR, which elongates loricrin by 22 amino acids because of delayed termination. As pseudoainhums are missing in all patients of the family reported, we propose two compulsory features of loricrin keratoderma: (i) honeycomb palmoplantar keratoderma and (ii) diffuse ichthyosiform dermatosis. Therefore we suggest that the condition should be described clinically as 'honeycomb palmoplantar keratoderma with ichthyosis'. Furthermore, we have assessed the amounts of transcript of LOR using pyrosequencing. This revealed an equal expression of mutant and wild-type alleles of LOR in an affected individual. These findings further underline the gain-of-function theory for mutant LOR in loricrin keratoderma.

Genetic diseases affecting the epidermis

Genetic diseases affecting the epidermis

Structural and Functional Consequences of Loricrin Mutations in Human Loricrin Keratoderma (Vohwinkel Syndrome with Ichthyosis)

Although loricrin is the predominant protein of the cornified envelope (CE) in keratinocytes, loss or gain of loricrin function in mouse models produces only modest skin phenotypes. In contrast, insertional mutations resulting in a frameshift in the C-terminal domain of loricrin produce the characteristic ichthyosis of loricrin keratoderma in mouse and man. To ascertain the basis for the loricrin keratoderma phenotype, we assessed epidermal structure and stratum corneum (SC) function in a previously genotyped human loricrin keratoderma kindred. Our studies revealed abnormal corneocyte fragility and basal permeability barrier function, but accelerated repair kinetics. Despite fragility, increased water loss occurred predominantly via extracellular domains, which correlated with disorganized lamellar bilayers that were linked spatially to discontinuities of the CE. Accelerated barrier recovery was explicable by amplified lamellar body secretion, while partial normalization of the CE in the outer SC correlated with persistence of abundant calcium in the extracellular spaces (positioned to activate transglutaminase-1). These results show that the barrier abnormality in loricrin keratoderma is linked to a defective CE scaffold, resulting in increased extracellular permeability, as shown previously for another "scaffold disorder", lamellar ichthyosis. But in contrast to lamellar ichthyosis, the CE scaffold partially normalizes in the outer SC in loricrin keratoderma.

Transgenic mice expressing a mutant form of loricrin reveal the molecular basis of the skin diseases, Vohwinkel syndrome and progressive symmetric erythrokeratoderma.

Mutations in the cornified cell envelope protein loricrin have been reported recently in some patients with Vohwinkel syndrome (VS) and progressive symmetric erythrokeratoderma (PSEK). To establish a causative relationship between loricrin mutations and these diseases, we have generated transgenic mice expressing a COOH-terminal truncated form of loricrin that is similar to the protein expressed in VS and PSEK patients. At birth, transgenic mice (ML.VS) exhibited erythrokeratoderma with an epidermal barrier dysfunction. 4 d after birth, high-expressing transgenic animals showed a generalized scaling of the skin, as well as a constricting band encircling the tail and, by day 7, a thickening of the footpads. Histologically, ML. VS transgenic mice also showed retention of nuclei in the stratum corneum, a characteristic feature of VS and PSEK. Immunofluorescence and immunoelectron microscopy showed the mutant loricrin protein in the nucleus and cytoplasm of epidermal keratinocytes, but did not detect the protein in the cornified cell envelope. Transfection experiments indicated that the COOH-terminal domain of the mutant loricrin contains a nuclear localization signal. To determine whether the ML.VS phenotype resulted from dominant-negative interference of the transgene with endogenous loricrin, we mated the ML.VS transgenics with loricrin knockout mice. A severe phenotype was observed in mice that lacked expression of wild-type loricrin. Since loricrin knockout mice are largely asymptomatic (Koch, P.K., P. A. de Viragh, E. Scharer, D. Bundman, M.A. Longley, J. Bickenbach, Y. Kawachi, Y. Suga, Z. Zhou, M. Huber, et al., J. Cell Biol. 151:389-400, this issue), this phenotype may be attributed to expression of the mutant form of loricrin. Thus, deposition of the mutant protein in the nucleus appears to interfere with late stages of epidermal differentiation, resulting in a VS-like phenotype.

Programmed cell death in normal epidermis and loricrin keratoderma. Multiple functions of profilaggrin in keratinization.

The terminal differentiation of epidermal keratinocytes has been regarded as an example of programmed cell death. Among the proteins specifically expressed in this process is profilaggrin, which consists offilaggrin repeats and N- and C-terminal domains. Profilaggrin is proteolytically processed into individual domains during the terminal differentiation. Filaggrin released from profilaggrin aggregates keratin filaments to form compacted cornified cells with a keratin pattern. A recent transfection experiment has indicated initiation of cell death by filaggrin expression constructs. The transitional cells between the granular and cornified cells show morphologic characteristics of apoptotic cells, and their nuclei contain fragmented DNA and profilaggrin N-terminal domains. This suggests that the N-terminus of profilaggrin may participate in nuclear events accompanying programmed cell death. Among inherited skin disorders with abnormal keratinization, progressive symmetric erythrokeratoderma is caused by loricrin mutation (loricrin keratoderma). In this disease, profilaggrin N-terminal domains are aggregated with mutant loricrin within condensed nuclei. These nuclei persist in the cornified layer as parakeratosis. Loricrin keratoderma could therefore be regarded as a representative form of disrupted cell death.