Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18q11.2 | Epidermolysis bullosa, junctional 2B, severe | 619784 | Autosomal recessive | 3 | LAMA3 | 600805 |
A number sign (#) is used with this entry because of evidence that severe junctional epidermolysis bullosa 2B (JEB2B) is caused by homozygous mutations in the LAMA3 gene (600805) on chromosome 18q11.
Severe junctional epidermolysis bullosa 2B (JEB2B) is an autosomal recessive skin blistering disorder characterized by extreme fragility of the skin and epithelia of various extracutaneous tissues. Skin blisters and erosions are present at birth. The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. Oral mucosal blistering and laryngeal and esophageal mucosal involvement can occur. Patients usually die before 1 year of age (summary by Has et al., 2020).
For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (226650).
Reviews
Has et al. (2020) reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa.
Kivirikko et al. (1995) described a 1-month-old male infant, the child of unaffected first-cousin parents of Asian ancestry, with JEB of the Herlitz type and mutation in the LAMA3 gene. At birth the child had extensive blistering of skin and mucous membranes. Indirect immunofluorescence showed essentially negative staining of the dermal-epidermal junction with GB3 antibody. Diagnostic transmission electron microscopy showed rudimentary hemidesmosomes, scanty subbasal dense plates, and few anchoring filaments. Blister formation was at the level of lamina lucida. The child died from complications of the disease in early infancy.
McGrath et al. (1995) studied a child of Pakistani origin with Herlitz-type JEB, the offspring of unaffected first-cousin parents, with mutation in the LAMA3 gene. Extensive blisters and erosions were present at examination shortly after birth. Electron microscopy of skin revealed scanty, rudimentary hemidesmosome-anchoring complexes and tissue separation within the lamina lucida. Immunofluorescence staining found absent labeling of the basement membrane zone with anti-laminin-5 antibody. A 2-month-old boy, also the child of unaffected first-cousin Pakistani parents, with Herlitz-type JEB studied by McGrath et al. (1996) had similar findings and died at 8 months of age. The children studied by Kivirikko et al. (1995), McGrath et al. (1995), and McGrath et al. (1996) all carried the same mutation in homozygosity, and haplotype analysis by McGrath et al. (1996) demonstrated propagation of an ancestral allele in the Pakistani population.
Nakano et al. (2002) reported 5 infants with Herlitz type JEB and mutation in the LAMA3 gene, all of whom died before 5 months of age. In addition to generalized blistering, oral involvement was reported in 2 patients, necessitating feeding tube and tracheostomy in 1. The individuals were identified in a cohort of 27 probands with JEB, 15 with the Herlitz subtype, and mutations in one of the laminin-5 subunit genes.
The transmission pattern of JEB2B in the families reported by Kivirikko et al. (1995), McGrath et al. (1995), and McGrath et al. (1996) was consistent with autosomal recessive inheritance.
In a patient with Herlitz JEB, Vidal et al. (1995) identified a homozygous 1-bp deletion in the LAMA3 gene (300delG; 600805.0001). The patient's parents were first cousins. Skin biopsies showed drastically reduced immunoreactivity to antibodies directed against the alpha-3 chain of laminin-5 and impaired expression of the corresponding mRNA transcripts.
In an infant boy with the lethal Herlitz form of junctional epidermolysis bullosa, Kivirikko et al. (1995) identified a homozygous nonsense mutation in the LAMA3 gene (R650X; 600805.0002).
McGrath et al. (1995) identified a homozygous R650X mutation in the LAMA3 gene in a Pakistani infant with Herlitz JEB. McGrath et al. (1996) identified the R650X mutation in homozygosity in another, apparently unrelated, Pakistani child. Haplotype analysis by McGrath et al. (1996) in their family and the families reported by Kivirikko et al. (1995) and McGrath et al. (1995) demonstrated propagation of an ancestral allele in the Pakistani population.
Ryan et al. (1999) observed that mice with targeted disruption of the murine Lama3 gene, had profound epithelial abnormalities resulting in neonatal lethality. The Lama3-null animals developed junctional blisters in the skin caused by a separation at the dermal-epidermal junction, similar to that observed in human Herlitz junctional epidermolysis bullosa.
Has, C., Bauer, J. W., Bodemer, C., Bolling, M. C., Bruckner-Tuderman, L., Diem, A., Fine, J. D., Heagerty, A., Hovnanian, A., Marinkovich, M. P., Martinez, A. E., McGrath, J. A., and 10 others. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. Brit. J. Derm. 183: 614-627, 2020. [PubMed: 32017015] [Full Text: https://doi.org/10.1111/bjd.18921]
Kivirikko, S., McGrath, J. A., Baudoin, C., Aberdam, D., Ciatti, S., Dunnill, M. G. S., McMillan, J. R., Eady, R. A. J., Ortonne, J.-P., Meneguzzi, G., Uitto, J., Christiano, A. M. A homozygous nonsense mutation in the alpha-3 chain gene of laminin 5 (LAMA3) in lethal (Herlitz) junctional epidermolysis bullosa. Hum. Molec. Genet. 4: 959-962, 1995. [PubMed: 7633458] [Full Text: https://doi.org/10.1093/hmg/4.5.959]
McGrath, J. A., Kivirikko, S., Ciatti, S., Moss, C., Christiano, A. M., Uitto, J. A recurrent homozygous nonsense mutation within the LAMA3 gene as a cause of Herlitz junctional epidermolysis bullosa in patients of Pakistani ancestry: evidence for a founder effect. J. Invest. Derm. 106: 781-784, 1996. [PubMed: 8618022] [Full Text: https://doi.org/10.1111/1523-1747.ep12346349]
McGrath, J. A., Kivirikko, S., Ciatti, S., Moss, C., Dunnill, M. G. S., Eady, R. A. J., Rodeck, C. H., Christiano, A. M., Uitto, J. A homozygous nonsense mutation in the alpha-3 chain gene of laminin 5 (LAMA3) in Herlitz junctional epidermolysis bullosa: prenatal exclusion in a fetus at risk. Genomics 29: 282-284, 1995. [PubMed: 8530087] [Full Text: https://doi.org/10.1006/geno.1995.1246]
Nakano, A., Chao, S.-C., Pulkkinen, L., Murrell, D., Bruckner-Tuderman, L., Pfendner, E., Uitto, J. Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs non-Herlitz phenotypes. Hum. Genet. 110: 41-51, 2002. [PubMed: 11810295] [Full Text: https://doi.org/10.1007/s00439-001-0630-1]
Ryan, M. C., Lee, K., Miyashita, Y., Carter, W. G. Targeted disruption of the LAMA3 gene in mice reveals abnormalities in survival and late stage differentiation of epithelial cells. J. Cell Biol. 145: 1309-1323, 1999. [PubMed: 10366601] [Full Text: https://doi.org/10.1083/jcb.145.6.1309]
Vidal, F., Baudoin, C., Miquel, C., Galliano, M.-F., Christiano, A. M., Uitto, J., Ortonne, J.-P., Meneguzzi, G. Cloning of the laminin alpha-3 chain gene (LAMA3) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa. Genomics 30: 273-280, 1995. [PubMed: 8586427] [Full Text: https://doi.org/10.1006/geno.1995.9877]