Novel ITGB4 Mutations in Lethal and Nonlethal Variants of Epidermolysis Bullosa with Pyloric Atresia: Missense versus Nonsense

Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Philadelphia, PA 19107, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 12/1998; 63(5):1376-87. DOI: 10.1086/302116
Source: PubMed


Epidermolysis bullosa with pyloric atresia (EB-PA), an autosomal recessive genodermatosis, manifests with neonatal cutaneous blistering associated with congenital pyloric atresia. The disease is frequently lethal, but nonlethal cases have also been reported. Expression of the alpha6 beta4 integrin is altered at the dermal-epidermal basement-membrane zone; recently, mutations in the corresponding genes (ITGA6 and ITGB4) have been disclosed in a limited number of patients, premature termination codons in both alleles being characteristic of lethal variants. In this study, we have examined the molecular basis of EB-PA in five families, two of them with lethal and three of them with nonlethal variants of the disease. Mutation analysis disclosed novel lesions in both ITGB4 alleles of each proband. One of the patients with lethal EB-PA was a compound heterozygote for premature termination-codon mutations (C738X/4791delCA), whereas the other patient with a lethal variant was homozygous for a missense mutation involving a cysteine residue (C61Y). The three nonlethal cases had missense mutations in both alleles (C562R/C562R, R1281W/R252C, and R1281W/R1281W). Immunofluorescence staining of skin in two of the nonlethal patients and in one of the lethal cases was positive, yet attenuated, for alpha6 and beta4 integrins. These results confirm that ITGB4 mutations underlie EB-PA and show that missense mutations may lead to nonlethal phenotypes.

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Available from: Leena Pulkkinen, Sep 30, 2015
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    • "Junctional epidermolysis bullosa (JEB) is a collection of recessive inherited disorders featuring skin fragility and AI caused by defects in genes encoding the components of hemidesmosome/basement-membrane complexes (Masunaga, 2006). JEB cases with well-described enamel defects have been reported for COL17A1 (McGrath et al., 1996; Pasmooij et al., 2007), ITGB4 (Pulkkinen et al., 1998), and genes encoding laminin-332, such as LAMB3 (Buchroithner et al., 2004). The enamel is characterized by deep pits and grooves that might increase the risk for dental caries (Wright et al., 1994). "
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    ABSTRACT: Amelogenesis imperfecta (AI) can be either isolated or part of a larger syndrome. Junctional epidermolysis bullosa (JEB) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms. JEB is a recessive syndrome usually caused by mutations in both alleles of COL17A1, LAMA3, LAMB3, or LAMC2. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomal-dominant amelogenesis imperfecta (ADAI) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits. Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of LAMB3 that likely truncated the protein. The mutations perfectly segregated with the enamel defects in both families. In Family 1, an 8-bp deletion (c.3446_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) generated an in-frame translation termination codon (p.Ser1144*). We conclude that enamel formation is particularly sensitive to defects in hemidesmosome/basement-membrane complexes and that syndromic and non-syndromic forms of AI can be etiologically related.
    Journal of dental research 08/2013; 92(10). DOI:10.1177/0022034513502054 · 4.14 Impact Factor
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    • "The initiation of enamel formation requires successful replacement of the basement membrane with the mineralization front apparatus. This does not occur properly when proteins associated with the basement membrane, such as collagen 17,11,12,13 α6/β4 integrin14,15,16 or laminin-33217,18,19,20 or proteins associated with the mineralization front, such as enamelin21 or ameloblastin,22,23 are defective or missing.24,25,26 Amelogenin (the most abundant enamel matrix protein) appears to be sparse at the mineralization front23,27,28 and a thin layer of enamel (∼15 µm vs. ∼110 µm) is deposited in AmelX knockout mice.29 "
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    ABSTRACT: Enamel crystals are unique in shape, orientation and organization. They are hundreds of thousands times longer than they are wide, run parallel to each other, are oriented with respect to the ameloblast membrane at the mineralization front and are organized into rod or interrod enamel. The classical theory of amelogenesis postulates that extracellular matrix proteins shape crystallites by specifically inhibiting ion deposition on the crystal sides, orient them by binding multiple crystallites and establish higher levels of crystal organization. Elements of the classical theory are supported in principle by in vitro studies; however, the classical theory does not explain how enamel forms in vivo. In this review, we describe how amelogenesis is highly integrated with ameloblast cell activities and how the shape, orientation and organization of enamel mineral ribbons are established by a mineralization front apparatus along the secretory surface of the ameloblast cell membrane.
    International Journal of Oral Science 09/2012; 4(3):129-34. DOI:10.1038/ijos.2012.59 · 2.53 Impact Factor
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    • "SM and HN2 also reduces tissue immunreactivity of laminin-332, as well as integrin a6b4 and BP230, two hemidesmosomal components that are critical for keratinocyte adherence (Kan et al., 2003; Smith et al., 1997b, 1998; Werrlein and Madren-Whalley, 2000; Zhang and Monteiro-Riviere, 1997). Interestingly, each of these ECM proteins, like keratins, has been implicated in human blistering disorders involving separation of the epidermis at the dermalepidermal junction (Pulkkinen et al., 1998; Yancey, 2005). These findings suggest that SM can alter the interaction of basal cells with matrix proteins that are critical for basement membrane adherence. "
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    ABSTRACT: Sulfur mustard (SM), a chemical weapon first employed during WorldWar I, targets the skin, eyes, and lung. It remains a significant military and civilian threat. The characteristic response of human skin to SM involves erythema of delayed onset, followed by edema with inflammatory cell infiltration, the appearance of large blisters in the affected area, and a prolonged healing period. Several in vivo and in vitro models have been established to understand the pathology and investigate the mechanism of action of this vesicating agent in the skin. SM is a bifunctional alkylating agent which reacts with many targets including lipids, proteins, and DNA, forming both intra-and intermolecular cross-links. Despite the relatively nonselective chemical reactivity of this agent, basal keratinocytes are more sensitive, and blistering involves detachment of these cells from their basement membrane adherence zones. The sequence and manner in which these cells die and detach is still unresolved. Much has been discovered over the past two decades with respect to the mechanisms of SM-induced cytotoxicity and the intracellular and extracellular targets of this vesicant. In this review, the effects of SM exposure on the skin are described, as well as potential mechanisms mediating its actions. Successful therapy for SM poisoning will depend on following new mechanistic leads to develop drugs that target one or more of its sites of action. © The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: [email protected] /* */
    Toxicological Sciences 10/2009; 114(1):5-19. DOI:10.1093/toxsci/kfp253 · 3.85 Impact Factor
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