LAMB3 mutations in generalized atrophic benign epidermolysis bullosa: Consequences at the mRNA and protein levels

Pulkkinen, Leena; Jonkman, Marcel F.; McGrath, John A.; Kuijpers, A.L.A.; Paller, A.S.; Uitto, Jouni

doi:10.1016/s0945-053x(98)90053-1

Cited by 13 publications

(21 citation statements)

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“…This change results, when compounded with premature termination of the second allele, in generalized atrophic benign epidermolysis bullosa. However, since this mutation also appears to alter splicing efficiency, resulting in marked reduction in the full-length transcript, the full importance of the LN domain in laminin-5 is still open to speculation (32,33). We could show that the native laminin-5, the only laminin known to contain the ␤ 3 chain, interacts with the ␥ isoforms in a manner similar to its recombinantly expressed LN domain.…”

Section: Laminin N-terminal Domains 44509mentioning

confidence: 88%

Molecular Analysis of Laminin N-terminal Domains Mediating Self-interactions

Odenthal

Haehn

Tunggal

et al. 2004

Journal of Biological Chemistry

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The ability of laminins to self-polymerize is crucial for the formation of basement membranes. Development of this polymerized network has profound effects upon tissue architecture as well as on the intracellular organization and differentiation of neighboring cells. The laminin N-terminal (LN) domains have been shown to mediate this interaction and studies using proteolytic fragments derived from laminin-1 led to the theory that network assembly depends on the formation of a heterotrimeric complex between LN domains derived from ␣, ␤, and ␥ chains in different laminin molecules with homologous interactions being insignificant. The laminin family consists of 15 known isoforms formed from five ␣, three ␤, and three ␥ chains, of which some are truncated and lack the N-terminal LN domain. To address whether the model of heterotrimeric complex formation is applicable to laminin isoforms other than laminin-1, eight LN domains found in the laminin protein family were recombinantly expressed and tested in three different assays for homologous and heterologous interactions. The results showed that the lack of homologous interactions is an exception, with such interactions being seen for LN domains derived from all ␣ chains and from the ␤ 2 and ␤ 3 subunits. The ␥ chain-derived LN domains showed a far more limited binding repertoire, particularly in the case of the ␥ 3 chain, which is found present in a range of non-basement membrane locations. Further, whereas the interactions depended upon Ca 2؉ ions, with EDTA reversibly abrogating binding, EDTA-induced conformational changes were not reversible. Together these results demonstrate that the assembly model proposed on the basis of laminin-1 may be a simplification, with the assembly of naturally occurring laminin networks being far more complex and highly dependent upon which laminin isoforms are present.Basement membranes are specialized extracellular matrices found underlying all epithelia and endothelia as well as surrounding many types of mesenchymal cells. Laminins constitute the major noncollagenous protein component within the basement membrane and are crucial for its formation (1, 2). Through their interactions with specific receptors, especially members of the ␤ 1 integrin family and ␣-dystroglycan, they induce many cellular effects, including differentiation and cellular and axonal migration. The prototype, laminin-1, isolated from embryonic carcinoma cells (3) or the Engelbreth-HolmSwarm tumor (4) has been shown to belong to a family consisting of 15 members (for nomenclature, see Refs. 5-7). Laminins are multidomain heterotrimers formed by the combination of one ␣, one ␤, and one ␥ chain. Laminin-1 is an 800-kDa glycoprotein composed of a 400-kDa ␣ 1 chain and ␤ 1 and ␥ 1 chains, each of 200 kDa. It has a cross structure with one long and three short arms, the latter being formed from the three free N-terminal ends of the ␣, ␤, and ␥ chains (8). These parts of the ␤ and ␥ chains each contain two globular domains, designated IV and VI, whereas there are three...

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Section: Laminin N-terminal Domains 44509mentioning

confidence: 88%

Molecular Analysis of Laminin N-terminal Domains Mediating Self-interactions

Odenthal

Haehn

Tunggal

et al. 2004

Journal of Biological Chemistry

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“…The disease is caused by genetic aberrations in genes encoding structural components of the cutaneous basement membrane zone (BMZ) such as hemidesmosomes, anchoring filaments and anchoring fibrils, which are critical for the stable attachment of the epidermis to the underlying dermis. Cases of EB are classified into four clinically distinct categories including simplex, junctional, dystrophic and the recently introduced hemidesmosomal (Pulkkinen et al 1998) variants, based on the level of tissue separation within the epidermal BMZ. The diagnosis is based on characteristic clinical features, transmission electron microscopy, immunoepitope mapping and the inheritance pattern (Fine et al 1999(Fine et al , 2000.…”

Section: Introductionmentioning

confidence: 99%

Novel and recurrent mutations in the laminin-5 genes causing lethal junctional epidermolysis bullosa: molecular basis and clinical course of Herlitz disease

et al. 2004

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Herlitz disease (H-JEB), the lethal form of junctional epidermolysis bullosa, is a rare genodermatosis presenting from birth with widespread erosions and blistering of skin and mucosae because of tissue cleavage within the epidermal basement membrane. Mutations in any of the three genes encoding the alpha3, beta3 and gamma2 chains of laminin-5 underlie this recessively inherited disorder. Here, we report the molecular basis and clinical course of H-JEB in 12 patients. Two novel nonsense mutations in the gene LAMA3 (E281X and K1299X) and a novel frame-shift mutation in the gene LAMB3 (1628insG) leading to a premature termination codon were identified by DNA sequencing and confirmed by restriction fragment length polymorphism analysis. In the four patients affected, neither the resulting truncated polypeptide chains nor assembled laminin-5 protein were detectable by immunofluorescence. Three patients were found to be heterozygous for the known hotspot mutation R635X and the recurrent mutations Q373X or 29insC in the gene LAMB3, whereas five others were homozygous for R635X. Significant variations in the disease progression and survival times between 1 and 30 months in this group of H-JEB patients emphasised the impact of modifying factors and the importance of immunostaining or mRNA assessment as parallel diagnostic methods. Interestingly, the only patients who survived for longer than 6 months were four females carrying the mutation R635X homozygously. In one of them, the clinical course may have been improved by treatment with artificial skin equivalents. These data may stimulate further investigation of genotype-phenotype correlations and facilitate mutation analysis and genetic counselling of affected families.

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“…Recent work in a patient homozygous for E210K provides supportive evidence for alternative transcripts arising from this mutation. 36 In summary, this report details the clinical features of two adult patients with the GABEB subtype of nonlethal junctional EB and a child with less pathognomonic clinical features. The underlying molecular pathology consists of an identical missense mutation E210K on one LAMB3 allele of each patient, accompanied by different nonsense mutations on the second allele.…”

Section: Discussionmentioning

confidence: 96%

E210K mutation in the gene encoding the β3 chain of laminin-5 (LAMB3) is predictive of a phenotype of generalized atrophic benign epidermolysis bullosa

Mellerio

Eady

Atherton

et al. 1998

British Journal of Dermatology

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Pathogenetic mutations in the genes encoding the hemidesmosome-anchoring filament complex proteins, laminin-5 and the 180 kDa bullous pemphigoid antigen, have been identified in patients with the inherited mechanobullous disease, junctional epidermolysis bullosa (EB). Furthermore, there is some evidence to suggest that precise definition of the nature of mutations in these genes may correlate to specific phenotypes of disease. We report three junctional EB patients who carry an identical missense mutation, E210K, on one allele of the gene encoding the beta3 subunit chain of laminin-5 (LAMB3) in addition to different nonsense mutations on the second allele. Two of the patients are adults and display a specific phenotype of non-lethal junctional EB known as generalized atrophic benign EB, which is associated with trauma-induced blisters, nail dystrophy and alopecia. As the third patient is a young child with fewer features of this subtype to date, identification of E210K in combination with a nonsense LAMB3 mutation may be predictive of the subsequent development of a generalized atrophic benign EB phenotype both in this child and in other junctional EB patients with the E210K mutation. Identification of this particular mutation has important implications for clinical management and counselling.

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LAMB3 mutations in generalized atrophic benign epidermolysis bullosa: Consequences at the mRNA and protein levels

Cited by 13 publications

References 0 publications

Molecular Analysis of Laminin N-terminal Domains Mediating Self-interactions

Molecular Analysis of Laminin N-terminal Domains Mediating Self-interactions

Novel and recurrent mutations in the laminin-5 genes causing lethal junctional epidermolysis bullosa: molecular basis and clinical course of Herlitz disease

E210K mutation in the gene encoding the β3 chain of laminin-5 (LAMB3) is predictive of a phenotype of generalized atrophic benign epidermolysis bullosa

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