Identification of a Homozygous One-Basepair Deletion in Exon 14 of the LAMB3 in a Patient with Herlitz Junctional Epidermolysis Bullosa and Prenatal Diagnosis in a Family at Risk for Recurrence

Vailly, Joëlle; Pulkkinen, Leena; Miquel, Corinne; Christiano, Angela M.; Gerecke, Donald R.; Burgeson, Robert E.; Uitto, Jouni; Ortonne, Jean‐Paul; Meneguzzi, Guerríno

doi:10.1111/1523-1747.ep12605898

Cited by 75 publications

(40 citation statements)

References 23 publications

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“…We have similarly shown that the presence of Type IV Collagen can support the early stage of BM maturation and lead to normalization of tissue organization and optimization of cell growth and survival. Thus, it appears that the balance between degradation and stabilization of newly synthesized BM components is essential for BM assembly and maturation (Amano et al 2001) It has been shown that pre-existing BM proteins serve as a template for the deposition and integration of newly synthesized proteins at the dermal-epidermal junction (Vailly et al, 1995). HSEs constructed by seeding keratinocytes on an interface containing pre-existing BM components, such as de-epithelialized skin (Andriani et al 2003) or amniotic membrane (Yang et al 2006) promote rapid assembly of well-structured BM.…”

Section: Discussionmentioning

confidence: 99%

The basement membrane microenvironment directs the normalization and survival of bioengineered human skin equivalents

Segal¹,

Andriani²,

Pfeiffer³

et al. 2008

Matrix Biology

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Epithelial-mesenchymal interactions promote the morphogenesis and homeostasis of human skin. However, the role of the basement membrane (BM) during this process is not well-understood. To directly study how BM proteins influence epidermal differentiation, survival and growth, we developed novel 3D human skin equivalents (HSEs). These tissues were generated by growing keratinocytes at an air-liquid interface on polycarbonate membranes coated with individual matrix proteins (Type I Collagen, Type IV Collagen or fibronectin) that were placed on contracted Type I Collagen gels populated with dermal fibroblasts. We found that only keratinocytes grown on membranes coated with the BM protein Type IV Collagen showed optimal tissue architecture that was similar to control tissues grown on de-epidermalized dermis (AlloDerm) that contained intact BM. In contrast, tissues grown on proteins not found in BM, such as fibronectin and Type I Collagen, demonstrated aberrant tissue architecture that was linked to a significant elevation in apoptosis and lower levels of proliferation of basal keratinocytes. While all tissues demonstrated a normalized, linear pattern of deposition of laminin 5, tissues grown on Type IV Collagen showed elevated expression of α6 integrin, Type IV Collagen and Type VII Collagen, suggesting induction of BM organization. Keratinocyte differentiation (Keratin 1 and filaggrin) was not dependent on the presence of BM proteins. Thus, Type IV Collagen acts as a critical microenvironmental factor in the BM that is needed to sustain keratinocyte growth and survival and to optimize epithelial architecture.

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Section: Discussionmentioning

confidence: 99%

The basement membrane microenvironment directs the normalization and survival of bioengineered human skin equivalents

Segal¹,

Andriani²,

Pfeiffer³

et al. 2008

Matrix Biology

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“…N-terminal amino acid sequence determinations were performed upon proteins transferred to polyvinylidene difluoride as previously reported (29,32). Fetal calf stomach skin was taken from a fetus determined by crown-rump measurements to be equivalent to the first to second trimester transition.…”

Section: Other Methodsmentioning

confidence: 99%

Bone Morphogenetic Protein 1 Is an Extracellular Processing Enzyme of the Laminin 5 γ2 Chain

Amano¹,

Scott²,

Takahara³

et al. 2000

Journal of Biological Chemistry

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209

192

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Epithelial cells maintained in culture medium containing low calcium proteolytically process laminin 5 (␣3␤3␥2) within the ␣3 and ␥2 chains (1). Experiments were designed to identify the enzyme(s) responsible for the laminin 5 processing and the sites of proteolytic cleavage. To characterize the nature of laminin 5 processing, we determined the N-terminal amino acid sequences of the proteolytic fragments produced by the processing events. The results indicate that the first ␣3 chain cleavage (200-l65 kDa ␣3) occurs within subdomain G4 of the G domain. The second cleavage (l65-l45 kDa ␣3) occurs within the lIla domain, 11 residues Nterminal to the start of domain II. The ␥ chain is cleaved within the second epidermal growth factor-like repeat of domain Ill. The sequence cleaved within the ␥2 chain matches the consensus sequence for the cleavage of type I, II, and III procollagens by bone morphogenetic protein-1 (BMP-1), also known as type I procollagen C-proteinase (2). Recombinant BMP-1 cleaves ␥2 in vitro, both within intact laminin 5 and at the predicted site of a recombinant ␥2 short arm. ␣3 is also cleaved by BMP-1 in vitro, but the cleavage site is yet to be determined. These results show the laminin ␣3 and ␥2 chains to be substrates for BMP-1 in vitro. We speculate that ␥2 cleavage is required for formation of the laminin 5-6 complex and that this complex is directly involved in assembly of the interhemidesmosomal basement membrane. This further suggests that BMP-1 activity facilitates basement membrane assembly, but not hemidesmosome assembly, in the laminin 5-rich dermalepidermal junction basement membrane in vivo.The occurrence of physiological, extracellular proteolytic processing of collagens is well documented, as is the important role that it plays in controlling the fibrillogenesis of banded collagen fibers (3). An enzyme responsible for removal of the C-terminal procollagen propeptides of the major fibrillar collagen types I-III has been identified as BMP-1 (2).1 BMP-1 was first identified in osteogenetic fractions of mammalian bone (4 -7) but was subsequently found to show substantial homology to proteins involved in morphogenetic patterning, such as the products of Drosophila genes tolloid (tld) and tlr-1 (12, 43) and of sea urchin gene products BP10 and SpAN (8, 9). Each contains an N-terminal astacin-like zinc-binding metalloendopeptidase domain (10) followed by varying numbers of epidermal growth factor-like (EGF-like) motifs and internal repeats termed CUB domains thought to be responsible for protein-protein interactions (44).There is abundant genetic and molecular evidence that Drosophila tld mediates dorsal-ventral patterning in the fly embryo (11-13), with null phenotypes of tld showing partial transformation of the dorsal ectoderm into ventral ectoderm (14). Genetic and developmental expression studies have also indicated that the tld gene product TLD participates within the same developmental pathway as the product of the decapentaplegic gene, DPP, the fly cognate of mammalian BMP-2 an...

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“…Além disso as complicações da fetoscopia com biópsia ocorrem entre quatro e 7% dos casos, e na biópsia coriôni-ca em 1%. 43 O seqüenciamento genético já foi utilizado no DPN de todas as formas de EB, 23,24,43,[49][50][51] já tendo sido também realizado antes da implantação, a partir de célula obtida de embrião com número de células variável de cinco a oito. 52 Aconselhamento genético é outra aplicação importante dessas novas informações, pois ajuda a esclarecer o padrão de herança, principalmente tratando-se de mutações freqüentes e bem conhecidas.…”

Section: Discussionunclassified

“…21,22 Semelhante às mutações dos componentes do hemidesmossoma descritas acima, as mutações da laminina também provocam o descolamento da epiderme. A maior parte das mutações dos gens da laminina 5 leva à PTC, provocando ausência da proteína e quadro clínico intenso, 23,24 caracterizado por lesões disseminadas afetando também as mucosas, 23 com sobrevida curta em função das complicações bacterianas, denominadas EBJ tipo Herlitz ou EBJ letal.…”

Section: Epidermólise Bolhosa Juncionalunclassified

Genética Molecular das Epidermólises Bolhosas

Almeida

2002

An. Bras. Dermatol.

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Resumo: O estudo das alterações moleculares das epidermólises bolhosas tem contribuído para que se compreenda melhor essas enfermidades. Na epidermólise bolhosa simples a maioria dos casos está associada com alteração nas citoqueratinas basais 5 (gen KRT5) e 14 (gen KRT14), o que modifica o citoesqueleto na camada basal da epiderme, levando à degeneração dessa camada, formando bolha intra-epidérmica. Mutações na plectina (gen PLEC1), componente da placa interna do hemidesmossoma, levam também à clivagem intra-epidérmi-ca. Na epidermólise bolhosa juncional vários gens estão envolvidos, em decorrência da complexidade da zona da membrana basal, todos levando ao descolamento dos queratinócitos basais na lâmina lúcida, pela disfunção da aderência entre esses e a lâmina densa. Alterações na laminina 5 (gens LAMA3, LAMB3 e LAMC2), integrina α6β4 (gens ITGA6 e ITGB4) e colágeno XVII (gen COL17A1) foram descritas. Por fim, na epidermólise bolhosa distrófica apenas um gen está mutado, alterando o colágeno VII (gen COL7A1), principal componente das fibrilas ancorantes, produzindo clivagem abaixo da lâmina densa, variando fenotipicamente de acordo com a conseqüência da mutação. Outra aplicação importante dessas informações refere-se ao diagnóstico pré-natal, com a perspectiva no futuro da terapia gênica. Palavras-chave: Diagnóstico pré-natal; epidermólise bolhosa; genética bioquímica; mutação; reação em cadeia da polimerase. KRT5) Summary: New data regarding the molecular aspects of the heterogeneous group of epidermolysis bullosa has brought some important information about its pathogenesis. In epidermolysis bullosa simplex the majority of mutations are localized in the genes of the basal cytokeratin 5 (gene

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Identification of a Homozygous One-Basepair Deletion in Exon 14 of the LAMB3 in a Patient with Herlitz Junctional Epidermolysis Bullosa and Prenatal Diagnosis in a Family at Risk for Recurrence

Cited by 75 publications

References 23 publications

The basement membrane microenvironment directs the normalization and survival of bioengineered human skin equivalents

The basement membrane microenvironment directs the normalization and survival of bioengineered human skin equivalents

Bone Morphogenetic Protein 1 Is an Extracellular Processing Enzyme of the Laminin 5 γ2 Chain

Genética Molecular das Epidermólises Bolhosas

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