PLoS One. 2012; 7(2): e31641
Ishida-Yamamoto A, Kishibe M, Murakami M, Honma M, Takahashi H, Iizuka H

Defects in epidermal barrier function and/or vesicular transport underlie severe skin diseases including ichthyosis and atopic dermatitis. Tight junctions (TJs) form a single layered network in simple epithelia. TJs are important for both barrier functions and vesicular transport. Epidermis is stratified epithelia and lamellar granules (LGs) are secreted from the stratum granulosum (SG) in a sequential manner. Previously, continuous TJs and paracellular permeability barriers were found in the second layer (SG2) of SG in mice, but their fate and correlation with LG secretion have been poorly understood. We studied epidermal TJ-related structures in humans and in mice and found occludin/ZO-1 immunoreactive multilayered networks spanning the first layer of SG (SG1) and SG2. Paracellular penetration tracer passed through some TJs in SG2, but not in SG1. LG secretion into the paracellular tracer positive spaces started below the level of TJs of SG1. Our study suggests that LG-secretion starts before the establishment of TJ barrier in the mammalian epidermis.

Arch Dermatol Res. 2012 Jan 19;
Dahlqvist J, Westermark GT, Vahlquist A, Dahl N

Autosomal recessive congenital ichthyosis (ARCI) is a group of disorders characterized by abnormal desquamation of the skin and a disrupted epidermal water barrier. Ichthyin/NIPAL4 gene mutations have been identified in a subgroup of ARCI patients, but the role of ichthyin in epidermis remains elusive. In order to obtain new insights concerning the characteristics of ichthyin and the ARCI pathogenesis, we studied the expression and localization of ichthyin and related epidermal components in cultured keratinocytes and skin sections from patients with Ichthyin mutations and healthy controls. We observed an up-regulation of Ichthyin mRNA levels after in vitro differentiation of keratinocytes from both a patient with Ichthyin mutations and controls. Confocal and electron microscopy analyses of immunolabeled skin sections revealed that ichthyin localizes to desmosomes and keratins in both patients with mutant Ichthyin and controls, with an increased immunolabeling in patients. Nile red lipid analysis of skin sections exposed intra-cellular lipid accumulations in cells of the granular and cornified layers in patients but not in controls, consistent with the pathognomonic lipid membrane structures previously identified in epidermis from patients. Our combined findings indicate that ichthyin is associated with keratins and desmosomes in epidermis and is involved in lipid metabolism, possibly through processing of lamellar bodies. These results provide new clues to the understanding of the epidermal water barrier and the pathogenesis in ARCI.

J Dermatol Sci. 2011 Dec 24;
Nakagawa N, Yamamoto M, Imai Y, Sakaguchi Y, Takizawa T, Ohta N, Yagi N, Hatta I, Hitomi K, Takizawa T, Takeda J, Tsuda T, Matsuki M, Yamanishi K

BACKGROUND: Mutations in the gene encoding transglutaminase 1 (TG1) are responsible for various types of autosomal recessive congenital ichthyosis (ARCI), such as lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) and some minor variants of ARCI. A point mutation of R143C in the β-sandwich domain of TG1 has been often identified in patients with LI or CIE. OBJECTIVE: To elucidate the effect of that point mutation on skin barrier structures and functions, we generated mice with a point mutation of R142C, which corresponds to the R143C mutation in human TG1. METHODS: A mouse line with the R142C point mutation in TG1 was established using a gene targeting technique and the Cre-loxP system. The skin phenotypes were analyzed in homozygous mutant Tgm1(R142C/R142C) mice. RESULTS: In the skin of Tgm1(R142C/R142C) mice, expression of the mutant transcripts was comparable with wild-type or Tgm1(+/R142C) mice. However, the amount of mutated protein in the skin was markedly decreased in Tgm1(R142C/R142C) mice, and the TG1 activity of Tgm1(R142C/R142C) keratinocytes was almost lost. Tgm1(R142C/R142C) mice exhibited morphological and functional skin barrier defects and neonatal lethality. The stratum corneum of those mice lacked cornified envelopes, and loricrin, the major structural component, failed to assemble at the corneocyte cell periphery. Tgm1(R142C/R142C) mice showed a marked increase in transepidermal water loss and their skin was easily permeable to toluidine blue dye. The intercellular lipid lamellar structures of the stratum corneum were irregular and the 13-nm periodic X-ray diffractions from the stratum corneum lipid molecules were lost in vivo. CONCLUSION: From these results, we suggest that the R142C mutation of TG1 reduces the enzyme stability which is indispensable for development of the stratum corneum and skin barrier function and for postnatal survival of mice.

Eur J Dermatol. 2012 Jan 17;
Nawaz S, Tariq M, Ahmad I, Malik NA, Baig SM, Dahl N, Klar J

A Mutations in the gene encoding the ABCA12 protein are associated with different subtypes of autosomal recessive congenital ichthyosis (ARCI), including Harlequin ichthyosis (HI), lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE). Disruption of ABCA12 lead to perturbed lipid transport in lamellar granules and a defective intercellular lipid layer of the stratum corneum. We have identified a large consanguineous Pakistani family affected by NCIE. Autozygosity mapping showed that affected individuals are homozygous for the ABCA12 gene region. Subsequent mutation screening revealed a homozygous c.4676G>T transition in all five affected family members. The mutation results in a novel p.G1559V substitution within the first nucleotide binding domain of ABCA12. The combined results support that an ABCA12 missense mutation, despite its location in a functional domain, may be associated with a mild ichthyosis phenotype. Furthermore, our findings increase the mutational spectrum in ABCA12 associated with ARCI of diagnostic and prognostic importance.

Nat Genet. 2012; 44(2): 140-7
Grall A, Guaguère E, Planchais S, Grond S, Bourrat E, Hausser I, Hitte C, Le Gallo M, Derbois C, Kim GJ, Lagoutte L, Degorce-Rubiales F, Radner FP, Thomas A, Küry S, Bensignor E, Fontaine J, Pin D, Zimmermann R, Zechner R, Lathrop M, Galibert F, André C, Fischer J

Ichthyoses comprise a heterogeneous group of genodermatoses characterized by abnormal desquamation over the whole body, for which the genetic causes of several human forms remain unknown. We used a spontaneous dog model in the golden retriever breed, which is affected by a lamellar ichthyosis resembling human autosomal recessive congenital ichthyoses (ARCI), to carry out a genome-wide association study. We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs. We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families. Further experiments highlighted the importance of PNPLA1 in the formation of the epidermal lipid barrier. This study identifies a new gene involved in human ichthyoses and provides insights into the localization and function of this yet uncharacterized member of the PNPLA protein family.

Acta Dermatovenerol Croat. 2011 Dec; 19(4): 268-70
Nenna R, D'Eufemia P, Celli M, Mennini M, Petrarca L, Zambrano A, Montuori M, La Pietra M, Bonamico M

We describe a 5-year-old female affected by lamellar ichthyosis, diagnosed in the first month of life, who attended our pediatric clinic for Mycoplasma pneumoniae pneumonia. The evidence of severe osteoporosis with hyperparathyroidism secondary to malabsorption suggested the occurrence of celiac disease. Endoscopy with multiple duodenal biopsies revealed total villous atrophy. The child started a gluten-free diet, supported by oral calcium and vitamin D. After 1-year follow-up, the girl showed complete normalization of bone mineral density. The introduction of the gluten-free diet did not lead to lesion repair, but the child reported significant improvement of her quality of life.

J Dermatol. 2011 Nov 21;
Alavi A, Shahshahani MM, Klotzle B, Fan JB, Ronaghi M, Elahi E

Ichthyosis is a heterogeneous disorder characterized by abnormal skin scaling over the whole body. Autosomal recessive congenital ichthyosis (ARCI) comprises various forms, the most important of which are lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). Seven genes have been identified to be causative of ARCI, and these account for disease in 60-80% of the patients. There is notable phenotypic overlap between the major forms of ARCI, and a strong genotype-phenotype correlation has not been found. Here, we initially aimed to identify the causative gene in a large Iranian ARCI pedigree, and subsequently performed genetic analysis on four other affected pedigrees. A genotype-phenotype correlation was sought. Whole genome homozygosity mapping using high-density single nucleotide polymorphism chips was performed on the large pedigree. Linkage to chromosome 5 and a mutation in NIPAL4 causing p.G297R were identified. The same mutation was also identified in two of the remaining four Iranian pedigrees. Two of the NIPAL4 mutation bearing pedigrees were classified as CIE and one as LI. Notably, all NIPAL4 mutation-bearing patients manifested diffuse yellowish keratoderma on the palms and soles. We provide evidence suggesting presentation of this diffuse yellowish keratoderma may be indicative of mutations in NIPAL4, providing an easily assessable genotype-phenotype correlation.

J Am Acad Dermatol. 2011 Oct 13;
Hernández-Martín A, Garcia-Doval I, Aranegui B, de Unamuno P, Rodríguez-Pazos L, González-Enseñat MA, Vicente A, Martín-Santiago A, Garcia-Bravo B, Feito M, Baselga E, Círia S, de Lucas R, Ginarte M, González-Sarmiento R, Torrelo A

BACKGROUND: Previous reports on the prevalence of autosomal recessive congenital ichthyosis (ARCI) were based on single source data, such as lists of members in a patient association. These sources are likely to be incomplete. OBJECTIVES: We sought to describe the prevalence of ARCI. METHODS: We obtained data from 3 incomplete sources (dermatology departments, a genetic testing laboratory, and the Spanish ichthyosis association) and combined them using the capture-recapture method. RESULTS: We identified 144 living patients with ARCI. Of these, 62.5% had classic lamellar ichthyosis and 30.6% had congenital ichthyosiform erythroderma. The age distribution included fewer elderly patients than expected. The prevalence of ARCI in patients younger than 10 years, the best estimate as less subject to bias, was 16.2 cases per million inhabitants (95% confidence interval 13.3-23.0). According to the capture-recapture model, 71% of the patients were not being followed up in reference units, 92% did not have a genetic diagnosis, and 78% were not members of the ichthyosis association. LIMITATIONS: The prevalence of ARCI in Spain and findings related to the Spanish health care system might not be generalizable to other countries. CONCLUSIONS: The prevalence of ARCI is higher than previously reported. Many patients are not being followed up in reference units, do not have a genetic diagnosis, and are not members of a patient association, indicating room for improvement in their care. Data suggesting a reduced number of older patients might imply a shorter life expectancy and this requires further study.

Clin Exp Obstet Gynecol. 2011; 38(3): 283-5
Basgul AY, Kavak ZN, Guducu N, Durukan B, Isci H

Harlequin fetus is a rare and mostly fatal form of congenital ichthyosis that can be diagnosed by fetal skin biopsy in patients with a family history of the disease. More recently DNA analysis of amniocentesis and chorion villus sampling materials have also been utilized. We report a case of prenatally diagnosed congenital ichthyosis with no previous family history. Diagnosis was mainly achieved by 3D and 4D ultrasonography findings such as diffuse scaling of the skin, digital contractures, flattened rudimentary external ear, nasal hypoplasia, everted eyelids, typical fish mouth appearance, macroglossia, and persistently open fetal mouth.

Essays Biochem. 2011 Sep 7; 50(1): 265-90
Quazi F, Molday RS

ABC (ATP-binding cassette) proteins actively transport a wide variety of substrates, including peptides, amino acids, sugars, metals, drugs, vitamins and lipids, across extracellular and intracellular membranes. Of the 49 hum an ABC proteins, a significant number are known to mediate the extrusion of lipids from membranes or the flipping of membrane lipids across the bilayer to generate and maintain membrane lipid asymmetry. Typical lipid substrates include phospholipids, sterols, sphingolipids, bile acids and related lipid conjugates. Members of the ABCA subfamily of ABC transporters and other ABC proteins such as ABCB4, ABCG1 and ABCG5/8 implicated in lipid transport play important roles in diverse biological processes such as cell signalling, membrane lipid asymmetry, removal of potentially toxic compounds and metabolites, and apoptosis. The importance of these ABC lipid transporters in cell physiology is evident from the finding that mutations in the genes encoding many of these proteins are responsible for severe inherited diseases. For example, mutations in ABCA1 cause Tangier disease associated with defective efflux of cholesterol and phosphatidylcholine from the plasma membrane to the lipid acceptor protein apoA1 (apolipoprotein AI), mutations in ABCA3 cause neonatal surfactant deficiency associated with a loss in secretion of the lipid pulmonary surfactants from lungs of newborns, mutations in ABCA4 cause Stargardt macular degeneration, a retinal degenerative disease linked to the reduced clearance of retinoid compounds from photoreceptor cells, mutations in ABCA12 cause harlequin and lamellar ichthyosis, skin diseases associated with defective lipid trafficking in keratinocytes, and mutations in ABCB4 and ABCG5/ABCG8 are responsible for progressive intrafamilial hepatic disease and sitosterolaemia associated with defective phospholipid and sterol transport respectively. This chapter highlights the involvement of various mammalian ABC transporters in lipid transport in the context of their role in cell signalling, cellular homoeostasis, apoptosis and inherited disorders.

Hip Int. 2011 Jul-Aug; 21(4): 487-9
Beazley JC, Ho K, Ilchyshyn A, Foguet P

Harlequin ichthyosis (HI) is a rare autosomal recessive skin disorder. No orthopaedic procedure has previously been described on a patient with HI. We report the case of a 17-year-old patient with HI who presented with bilateral juvenile idiopathic arthritis of the hips who underwent bilateral total hip replacements. Our standard operative and postoperative regime was followed and no complications occurred. One year after the second procedure our patient had a Oxford hip score of 43 and was very satisfied with the result.

Nagoya J Med Sci. 2011 Aug; 73(3-4): 79-90
Akiyama M

Research into the molecular genetics and pathomechanisms of ichthyoses have advanced considerably, resulting in the identification of several causative genes and molecules underlying the disease. In 2009, the First Ichthyosis Consensus Conference was held to establish a consensus for the nomenclature and classification of inherited ichthyoses, by which an international consensus for the classification of inherited ichthyosis was achieved. In this review, the pathogeneses of various ichthyoses are summarized based on their revised classification and terminology. Skin barrier defects are involved in the pathogenesis of various types of ichthyosis. The known causative molecules underlying ichthyosis include ABCA12, lipoxygenase-3, 12R-lipoxygenase, CYP4F22, ichthyin and steroid sulfatase, all of which are thought to be related to the intercellular lipid layers. ABCA12 is a known keratinocyte lipid transporter associated with lipid transport in lamellar granules and a loss of ABCA12 function leads to defective lipid transport in the keratinocytes, resulting in the most severe, harlequin ichthyosis phenotype. Other causative molecules for ichthyoses are transglutaminase 1, keratins and filaggrin. Transglutaminase 1 plays a role in cornified cell envelope formation. Keratins 1, 10 and 2 are involved in the keratin network of suprabasal keratinocytes and filaggrin is essential for the formation of keratohyalin granules. It is important to obtain information concerning genetic defects and to elucidate ichthyotic disease pathomechanisms for the establishment of an effective therapy and beneficial genetic counseling, including a prenatal diagnosis for families affected by ichthyotic disease.