Molecular diagnostics facilitate distinction between lethal and non-lethal subtypes of junctional epidermolysis bullosa: a case report and review of the literature

Bauer, Jürgen; Schumann, Hauke; Sönnichsen, Karsten; Tomaske, Maren; Bosk, Axel; Bruckner‐Tuderman, Leena; Rassner, G.; Garbe, Claus

doi:10.1007/s00431-001-0851-2

Cited by 17 publications

(11 citation statements)

References 26 publications

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“…We also tested the quantitative relationship between barrier integrity and WBC using a milder model of skin disruption. Junctional epidermolysis bullosa (JEB) is a skin blistering disease, most often caused by mutations in one of the three chains of laminin (Lm)-332, the α3, β3, or γ2 chains [60][61][62][63][64][65][66] . Mice that lack expression of Lm-332 die shortly after birth with blistering of the skin and oral mucosa [67][68][69] .…”

Section: Tsea Indicates Skin-expressed Loci Are Key Regulators Of Whimentioning

confidence: 99%

The anatomical distribution of genetic associations

Wells

Kopp

et al. 2015

Preprint

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Deeper understanding of the anatomical intermediaries for disease and other complex genetic traits is essential to understanding mechanisms and developing new interventions. Existing ontology tools provide functional, curated annotations for many genes and can be used to develop mechanistic hypotheses; yet information about the spatial expression of genes may be equally useful in interpreting results and forming novel hypotheses for a trait. Therefore, we developed an approach for statistically testing the relationship between gene expression across the body and sets of candidate genes from across the genome. We validated this tool and tested its utility on three applications. First, we show that the expression of genes in associated loci from GWA studies implicates specific tissues for 57 out of 98 traits. Second, we tested the ability of the tool to identify novel relationships between gene expression and phenotypes. Specifically, we experimentally confirmed an underappreciated prediction highlighted by our tool: that white blood cell count -a quantitative trait of the immune system -is genetically modulated by genes expressed in the skin. Finally, using gene lists derived from exome sequencing data, we show that human genes under selective constraint are disproportionately expressed in nervous system tissues.

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Section: Tsea Indicates Skin-expressed Loci Are Key Regulators Of Whimentioning

confidence: 99%

The anatomical distribution of genetic associations

Wells

Kopp

et al. 2015

Preprint

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“…In the most severe cases, infants do not survive beyond their first year of life. JEB is most often (88%) caused by the absence of laminin (Lm)-332, due to mutations in one of the three Lm-332 chains, the α3, ß3, or γ2 chains [1]–[6]. Lm-332 is normally secreted by skin keratinocytes and is a critical component of the BMZ between the epidermis and the dermal layer [7]–[9].…”

Section: Introductionmentioning

confidence: 99%

Keratinocyte-Targeted Expression of Human Laminin γ2 Rescues Skin Blistering and Early Lethality of Laminin γ2 Deficient Mice

et al. 2012

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Laminin-332 is a heterotrimeric basement membrane component comprised of the α3, ß3, and γ2 laminin chains. Laminin-332 modulates epithelial cell processes, such as adhesion, migration, and differentiation and is prominent in many embryonic and adult tissues. In skin, laminin-332 is secreted by keratinocytes and is a key component of hemidesmosomes connecting the keratinocytes to the underlying dermis. In mice, lack of expression of any of the three Laminin-332 chains result in impaired anchorage and detachment of the epidermis, similar to that seen in human junctional epidermolysis bullosa, and death occurs within a few days after birth. To bypass the early lethality of laminin-332 deficiency caused by the knockout of the mouse laminin γ2 chain, we expressed a dox-controllable human laminin γ2 transgene under a keratinocyte-specific promoter on the laminin γ2 (Lamc2) knockout background. These mice appear similar to their wild-type littermates, do not develop skin blisters, are fertile, and survive >1.5 years. Immunofluorescence analyses of the skin showed that human laminin γ2 colocalized with mouse laminin α3 and ß3 in the basement membrane zone underlying the epidermis. Furthermore, the presence of “humanized” laminin-332 in the epidermal basement membrane zone rescued the alterations in the deposition of hemidesmosomal components, such as plectin, collagen type XVII/BP180, and integrin α6 and ß4 chains, seen in conventional Lamc2 knockout mice, leading to restored formation of hemidesmosomes. These mice will be a valuable tool for studies of organs deficient in laminin-332 and the role of laminin-332 in skin, including wound healing.

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“…Specifically, global analysis of laminin-5 mutation database indicates that null mutations in the LAMA3, LAMB3, or LAMC2 genes encoding for the laminin-5 a3, b3, and g2 chains lead to the absence of laminin-5 that correlates with rudimentary/absent HD and severe defects in epithelial cell adhesion. These features are the hallmarks of the lethal Herlitz JEB variant (H JEB, OMIM 226700) (Pulkkinen et al, 1997b;Bauer et al, 2002). Other mutations, in most cases missense or in frame deletions in one or both alleles of the laminin-5 genes, cause a reduced expression of aberrant laminin-5 molecules that retain a residual biological activity, which results in the limited tendency to blistering distinctive of the mild non-Herlitz JEB (non-H JEB, OMIM 226650) (Posteraro et al, 1998;Castiglia et al, 2001, Nakano et al, 2002aScaturro et al, 2003).…”

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confidence: 95%

Laminin-5 Mutational Analysis in an Italian Cohort of Patients with Junctional Epidermolysis Bullosa

Posteraro

Luca

Meneguzzi

et al. 2004

Journal of Investigative Dermatology

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Junctional epidermolysis bullosa (JEB) is a rare genodermatosis characterized by dermal-epidermal separation that is caused by mutations in the genes encoding hemidesmosomal components and laminin-5, the major epithelial adhesion ligand. Here, we report on the mutational analysis of LAMA3, LAMB3, and LAMC2 genes encoding laminin-5 chains in 19 Italian patients, 11 affected with the severe Herlitz (H JEB) and eight with the mild non-Herlitz variant of JEB (non-H JEB). Eighteen mutations, seven of which were novel, were identified and their consequences analyzed at the mRNA and protein level. Premature termination codon mutations in both alleles of LAMB3 or LAMC2 genes were found in nine of the 11 H JEB patients, with a prevalence of mutations in LAMC2. In one case, a homozygous frameshift mutation in LAMB3 was associated to illegitimate splicing leading to non-H JEB. One H JEB patient showed a large intragenic duplication within LAMC2, a genetic defect so far uncovered in laminin-5 genes. Splicing or missense mutations, were prevalent in non-H JEB patients. Collectively, five mutations appeared to be frequent in laminin-5 JEB patients: R635X, 29insC, E210K, W143X in LAMB3 and R95X in LAMC2. These recurrent mutations account for approximately 44% of laminin-5 JEB alleles in Italian patients.

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Molecular diagnostics facilitate distinction between lethal and non-lethal subtypes of junctional epidermolysis bullosa: a case report and review of the literature

Cited by 17 publications

References 26 publications

The anatomical distribution of genetic associations

The anatomical distribution of genetic associations

Keratinocyte-Targeted Expression of Human Laminin γ2 Rescues Skin Blistering and Early Lethality of Laminin γ2 Deficient Mice

Laminin-5 Mutational Analysis in an Italian Cohort of Patients with Junctional Epidermolysis Bullosa

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