---Epidermolysis Bullosa, Junctional, non-Herlitz Type
The non-Herlitz form of junctional epidermolysis bullosa (226650) is usually inherited as an autosomal recessive disorder. McGrath et al. (1995) described a 14-year-old male with typical clinical features of the disorder. The parents, who were not related, were clinically normal. The patient was found to be a compound heterozygote for a premature termination mutation of both alleles of the BPAG2 gene: a paternally inherited C-to-T transition at nucleotide 3781 of their clone that converted an arginine residue to a nonsense codon (R1226X), and a maternally inherited 1-bp insertion of G at nucleotide position 4150 (113811.0002) that resulted in a frameshift and premature termination codon 50 nucleotides downstream from the site of insertion. The 2 mutations in BPAG2 were symbolized R1226X and 4150insG by the authors.
---Epidermolysis Bullosa, Junctional, Localisata Variant
In a 34-year-old male with the localisata variant of junctional epidermolysis bullosa (see 226650), the offspring of healthy nonconsanguineous Polish parents, Floeth et al. (1998) found heterozygosity for an R1226X mutation in the COL17A1 gene, resulting from a C-to-T transition at nucleotide 3781. The patient had nonscarring blistering since birth, initially generalized but later localized to the distal extremities. During the course of the disease, a slight hyperpigmentation of the skin and dystrophy of the toenails developed. No dental anomalies were observed, but the patient had a tendency to dental caries. The scalp and body hair was completely normal. The same mutation had previously been reported in GABEB families from the U.K., Holland, and Germany (McGrath et al., 1995; Jonkman et al., 1997; Schumann et al., 1997). R1226X may represent a mutation hotspot.
Floeth and Bruckner-Tuderman (1999) described a family with severe nonlethal junctional epidermolysis bullosa who had mutations in both the laminin-5, beta-3 subunit (LAMB3; 150310), and COL17A1 genes. The index patient, a 2-year-old boy, was compound heterozygous for the COL17A1 mutations leu855 to ter (L855X; 113811.0012) and R1226X, and heterozygous for the LAMB3 mutation R635X (150310.0001). As a consequence, 2 functionally related proteins were affected. Absence of collagen XVII and attenuated laminin-5 expression resulted in rudimentary hemidesmosome structure and separation of the epidermis from the basement membrane, with severe skin blistering as the clinical manifestation. In contrast, single heterozygotes carrying either (1) one or the other of the COL17A1 null alleles or (2) a double heterozygote for a COL17A1 and a LAMB3 null allele did not have a pathologic skin phenotype. These observations indicated that the known allelic heterogeneity in JEB is further complicated by interactions between unlinked mutations. They also demonstrated that identification of 1 mutation in 1 gene is not sufficient for determination of the genetic basis of JEB in a given family.
