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JMD 2005, Vol. 7, No. 1
Copyright © 2005 American Society for Investigative Pathology & Association for Molecular Pathology

Epidermolysis Bullosa Simplex Associated with Pyloric Atresia Is a Novel Clinical Subtype Caused by Mutations in the Plectin Gene (PLEC1)

Hiroyuki Nakamura*, Daisuke Sawamura*, Maki Goto*, Hideki Nakamura*, James R. McMillan*, Susam Park{dagger}, Sumio Kono{ddagger}, Shiro Hasegawa{ddagger}, Son’e Paku§, Tomohiko Nakamura§, Yoshihumi Ogiso and Hiroshi Shimizu*

From the Department of Dermatology, * Hokkaido University Graduate School of Medicine, Sapporo, Japan; the Division of Plastic Surgery {dagger} and the Division of Pediatric Surgery, {ddagger} Shizuoka Children’s Hospital, Shizuoka, Japan; and the Division of Neonatology § and the Division of Clinical Pathology, Nagano Children’s Hospital, Toyoshina, Japan

Epidermolysis bullosa (EB) is an inherited mechano-bullous disorder of the skin, and is divided into three major categories: EB simplex (EBS), dystrophic EB, and junctional EB (JEB). Mutations in the plectin gene (PLEC1) cause EBS associated with muscular dystrophy, whereas JEB associated with pyloric atresia (PA) results from mutations in the {alpha}6 and ß4 integrin genes. In this study, we examined three EB patients associated with PA from two distinct families. Electron microscopy detected blister formation within the basal keratinocytes leading to the diagnosis of EBS. Surprisingly, immunohistochemical studies using monoclonal antibodies to a range of basement membrane proteins showed that the expression of plectin was absent or markedly attenuated. Sequence analysis demonstrated four novel PLEC1 mutations. One proband was a compound heterozygote for a nonsense mutation of Q305X and a splice-site mutation of 1344G->A. An exon-trapping experiment suggested that the splice-site mutation induced aberrant splicing of the gene. The second proband harbored a heterozygous maternal nonsense mutation, Q2538X and homozygous nonsense mutations R1189X. Analysis of the intragenic polymorphisms of PLEC1 suggested that R1189X mutations were due to paternal segmental uniparental isodisomy. These results indicate that PLEC1 is a possible causative gene in this clinical subtype, EBS associated with PA. Furthermore, two patients out of our three cases died in infancy. In terms of clinical prognosis, this novel subtype is the lethal variant in the EBS category.




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R Varki, S Sadowski, E Pfendner, and J Uitto
Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants
J. Med. Genet., August 1, 2006; 43(8): 641 - 652.
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