Epidermolysis bullosa (EB) can be inherited in either autosomal recessive or autosomal dominant fashion and this depends primarily on the type of EB.
The disease is caused by mutations in structural proteins that are key for maintaining the integrity of the skin’s basement membrane zone or dermoepidermal junction.
Of particular importance in terms of severity of disease are the type of mutation and the location of the targeted protein within the keratin filament.
The four main types of EB are dystrophic epidermolysis bullosa (DEB), epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB), and Kindler syndrome (KS) and they all have varying mutation types.
DEB can be inherited either in an autosomal dominant (DDEB) or autosomal recessive (RDEB) pattern and accounts for 25% of EB cases.
The three main common subtypes of DEB are DDEB generalized (DDEB-G), RDEB generalized severe (RDEB-GS), and RDEB generalized intermediate (RDEB-GI).
Four major types of EBS, which account for up to 75% of all EB cases, have been identified: Weber-Cockayne type (EBS-WC), Dowling-Meara type (EBS-DM), Koebner type (EBS-K) and the mottled type (EBS-M).
JEB accounts for 5% of EB cases and has two main types: Herlitz JEB (JEB-H), the more severe of the two, and non-Herlitz JEB (JEB-nH).
Molecular Basis of EB Inheritance
Generally, extracutaneous disease and the severity of the skin involvement are a reflection of the type of mutation and the location of the targeted protein. DDEB-G, RDEB-GS, and RDEB-GI all result from collagen type VII gene (COL7A1) mutations.
DDEB mutations are usually missense (point mutations in which changing a single nucleotide results in the formation of a different amino acid). RDEB mutations, on the other hand, result in the formation of premature termination codons (i.e., they are nonsense mutations).
Localized EBS-WC and the other subtypes, EBS-K, EBS-DM, and EBS-M result from mutations in the keratin 5 or keratin 14 genes that are dominant negative. EBS-DM mutations tend to occur in regions of the keratin filament that are particularly sensitive structural domains.
Patients that present with pyloric atresia are found to have mutations in genes that code for plectin or transmembrane integrin proteins.
EBS-superficilias, a subtype of EBS, is thought to have a similar mutation in collagen type VII gene like that seen in DDEB. However, no detectable collagen type VII probands have been found in the mutation.
JEB-H arises due to mutations in any of the three genes that code for the adhesion molecule laminin-332, formerly known as laminin-5.
JEB-H presents with many mutational ‘hotspots’ that enable rapid DNA screening in the patients who are affected. Less severe mutations are found in the majority of JEB-nH cases within the same genes.
Few JEB-nH patients have mutations within another gene that was previously called bullous pemphigoid antigen and codes for type XVII collagen. KS is acquired through mutations in the gene for kindling-1. It is a very rare and recently discovered component of keratinocytes.