Differential Expression of Pyloric Atresia in Junctional Epidermolysis Bullosa with ITGB4 Mutations Suggests that Pyloric Atresia is due to Factors Other than the Mutations and Not Predictive of a Poor Outcome: Three Novel Mutations and a Review of the Li

Abstract

Junctional epidermolysis bullosa with pyloric atresia (JEB-PA) is an autosomal recessive blistering disease including lethal and non-lethal variants due to mutations in ITGB4 and ITGA6. It is unclear whether PA is caused directly by the mutations in these genes or by other factors. Skin biopsies from patients with JEB were processed for immunofluorescence mapping. When staining for integrin beta4 or alpha6 was absent or reduced, ITGB4 was screened for mutations. A review of known mutations of ITGB4 and the phenotypes of patients with JEB-PA was undertaken. Three novel ITGB4 mutations were identified in 3 families with JEB-PA: 2 splice-site and one insertion mutation. Two families with lethal phenotypes (EB-050 and EB-049) were due to combinations of premature termination codons and missense mutations (658delC/R252C and 3903dupC/G273D, respectively). The third family EB-013 has 2 JEB affected siblings; a brother with PA and a sister without PA. Both were homo notzygous for ITGB4 264G>A/3111-1G>A. Two cases had no gastrointestinal symptoms or signs of PA. PA is an inconstant feature of the subtype of epidermolysis bullosa known as JEB-PA. It is most likely that multiple factors influence the development of PA and its presence is not predictive of a poor outcome. It is possible that institutions that do not routinely screen immunofluore notscence mapping for integrin alpha6beta4 staining in the absence of PA are missing this form of epidermolysis bullosa.

ITGB4-associated Junctional Epidermolysis Bullosa without Pylori Atresia but Profound Genito-urinary Involvement

“…Of only 8 ITGB4-associated JEB cases without PA reported to date (3,4,(7)(8)(9), 2 had generalised blistering tendency (4,9), while other 6 had localised and mild skin involvement (3,(7)(8)(9). Notably, our patient presented with very mild blistering since birth and his skin was free of blistering after the age of 34 months.…”

“…Integrin α6β4 functions as a transmembrane receptor that is predominantly expressed in skin, gastrointestinal and urinary epithelia (3,7). This non-covalent adhesive heterodimer, together with plectin and laminin-332, provides the integrity and stability to the HD anchoring complex (10).…”

Transmembrane collagen XVII is a novel component of the glomerular filtration barrier

“…Based on the data of the National EB Registry, renal failure might occur in junctional EB, although mainly for secondary reasons (Fine et al 2004;Almaani and Mellerio 2010). Hereditary nephritis has been found in junctional EB with pyloric atresia caused by mutations in the β4 integrin gene; however, only a minority of patients with ITGB4 mutations have renal involvement (Kambham et al 2000;Dang et al 2008;Almaani and Mellerio 2010). β4-integrin null mice die immediately after birth because of the denuding of the skin but the renal consequences of β4-integrin knockout in mice have Fig.…”

Long-term Follow-up of a Spontaneously Improving Patient with Junctional Epidermolysis Bullosa Associated with ITGB4 c.3977-19T>A Splicing Mutation

“…In most cases, affected children die of systemic complications despite the surgical correction of the foregut obstruction (3). However, non-lethal forms of JEB-PA have also been reported (4,5). JEB-PA is caused by mutations in either of 2 genes coding for a6ß4 integrin {ITGA6, ITGB4) (2,6).…”