Autosomal Recessive Epidermolysis Bullosa Simplex Due to Loss of BPAG1-e Expression

Liu, Lu; Dopping-Hepenstal, Patricia J.C.; Lovell, Patricia A.; Michael, Magdalene; Horn, H. M.; Fong, Kenneth; Lai-Cheong, Joey; Mellerio, Jemima E.; Parsons, Maddy; McGrath, John A.

doi:10.1038/jid.2011.379

Cited by 56 publications

(68 citation statements)

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“…Furthermore, the mice show abnormal wound healing related to a reduced keratinocyte migration. In analogy, in humans homozygous nonsense mutations in DST specifically affecting BPAG1e result in EBS with fragility of basal keratinocytes, lack of hemidesmosomal plaques and trauma‐induced skin blistering . In apparent contrast with the studies performed in DST ‐knockout mice, cultured primary keratinocytes obtained from a patient with EBS caused by DST mutations specifically affecting BPAG1e show decreased cell‐substrate adhesion and increased migration.…”

Section: Bpag1e a Specialized Component Of Hdsmentioning

confidence: 97%

One gene but different proteins and diseases: the complexity of dystonin and bullous pemphigoid antigen 1

Künzli

Favre

Chofflon³

et al. 2015

Experimental Dermatology

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Since the immunochemical identification of the bullous pemphigoid antigen 230 (BP230) as one of the major target autoantigens of bullous pemphigoid (BP) in 1981, our understanding of this protein has significantly increased. Cloning of its gene, development and characterization of animal models with engineered gene mutations or spontaneous mouse mutations have revealed an unexpected complexity of the gene encoding BP230. The latter, now called dystonin (DST), is composed of at least 100 exons and gives rise to three major isoforms, an epithelial, a neuronal and a muscular isoform, named BPAG1e (corresponding to the original BP230), BPAG1a and BPAG1b, respectively. The various BPAG1 isoforms play a key role in fundamental processes, such as cell adhesion, cytoskeleton organization, and cell migration. Genetic defects of BPAG1 isoforms are the culprits of epidermolysis bullosa and complex, devastating neurological diseases. In this review, we summarize recent advances of our knowledge about several BPAG1 isoforms, their role in various biological processes and in human diseases.

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Section: Bpag1e a Specialized Component Of Hdsmentioning

confidence: 97%

One gene but different proteins and diseases: the complexity of dystonin and bullous pemphigoid antigen 1

Künzli

Favre

Chofflon³

et al. 2015

Experimental Dermatology

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“…Dst -null mice showed also discrete signs of skin blistering as a result of an impaired attachment of keratin IFs to hemidesmosomes in basal keratinocytes due to the absence of BPAG1e [21]. In humans, by analogy, homozygous nonsense DST mutations affecting BPAG1e result in epidermolysis bullosa simplex with fragility of basal keratinocytes and skin blistering [22], [23].…”

Section: Introductionmentioning

confidence: 99%

BPAG1a and b Associate with EB1 and EB3 and Modulate Vesicular Transport, Golgi Apparatus Structure, and Cell Migration in C2.7 Myoblasts

et al. 2014

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BPAG1a and BPAG1b (BPAG1a/b) constitute two major isoforms encoded by the dystonin (Dst) gene and show homology with MACF1a and MACF1b. These proteins are members of the plakin family, giant multi-modular proteins able to connect the intermediate filament, microtubule and microfilament cytoskeletal networks with each other and to distinct cell membrane sites. They also serve as scaffolds for signaling proteins that modulate cytoskeletal dynamics. To gain better insights into the functions of BPAG1a/b, we further characterized their C-terminal region important for their interaction with microtubules and assessed the role of these isoforms in the cytoskeletal organization of C2.7 myoblast cells. Our results show that alternative splicing does not only occur at the 5′ end of Dst and Macf1 pre-mRNAs, as previously reported, but also at their 3′ end, resulting in expression of additional four mRNA variants of BPAG1 and MACF1. These isoform-specific C-tails were able to bundle microtubules and bound to both EB1 and EB3, two microtubule plus end proteins. In the C2.7 cell line, knockdown of BPAG1a/b had no major effect on the organization of the microtubule and microfilament networks, but negatively affected endocytosis and maintenance of the Golgi apparatus structure, which became dispersed. Finally, knockdown of BPAG1a/b caused a specific decrease in the directness of cell migration, but did not impair initial cell adhesion. These data provide novel insights into the complexity of alternative splicing of Dst pre-mRNAs and into the role of BPAG1a/b in vesicular transport, Golgi apparatus structure as well as in migration in C2.7 myoblasts.

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“…However, the disease is genetically heterogeneous with about 25-30% of patients lacking mutations in those genes (Rugg et al, 2007;Bolling et al, 2011;Bruckner-Tuderman and Has, 2012). Well-defined subtypes of EBS are associated with typical clinical features and molecular pathology, but patients with mild skin fragility often exhibit less characteristic features rendering the determination of the candidate gene difficult (Groves et al, 2010;Liu et al, 2012;Pigors et al, 2012;Kiritsi et al, 2013). Recently, a homozygous frameshift mutation in the exophilin-5 gene (EXPH5) was identified in three individuals of a consanguineous Iraqi family with mild skin fragility (McGrath et al, 2012).…”

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confidence: 98%

Molecular Heterogeneity of Epidermolysis Bullosa Simplex: Contribution of EXPH5 Mutations

Pigors

Schwieger‐Briel

Leppert

et al. 2014

Journal of Investigative Dermatology

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Autosomal Recessive Epidermolysis Bullosa Simplex Due to Loss of BPAG1-e Expression

Cited by 56 publications

References 9 publications

One gene but different proteins and diseases: the complexity of dystonin and bullous pemphigoid antigen 1

One gene but different proteins and diseases: the complexity of dystonin and bullous pemphigoid antigen 1

BPAG1a and b Associate with EB1 and EB3 and Modulate Vesicular Transport, Golgi Apparatus Structure, and Cell Migration in C2.7 Myoblasts

Molecular Heterogeneity of Epidermolysis Bullosa Simplex: Contribution of EXPH5 Mutations

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