ITGA6 – junctional epidermolysis bullosa with pyloric atresia

Junctional epidermolysis bullosa with pyloric atresia (PA-JEB) is a rare autosomal recessive disorder characterized by mucocutaneous blistering and congenital gastric outlet obstruction. The integrin α6 subunit, encoded by ITGA6, forms the α6β4 heterodimer essential for hemidesmosome integrity at the dermal–epidermal junction.

Biallelic ITGA6 variants have been reported in 7 affected individuals from 5 unrelated families, confirming autosomal recessive inheritance ([PMID:9185503], [PMID:10701857], [PMID:14675179], [PMID:27607025], [PMID:9158140]). A consanguineous pedigree with three homozygous siblings demonstrated complete segregation, providing strong familial support ([PMID:9158140]).

The variant spectrum includes frameshift and splice‐site mutations leading to premature termination codons and null alleles, as well as missense substitutions within key domains. For example, c.286C>T (p.Arg96Trp) alters the β-propeller head of α6, triggering rapid lysosomal degradation and absence of functional integrin ([PMID:14675179]).

Functional studies consistently demonstrate absent or markedly reduced α6 and β4 integrin staining by immunofluorescence and disrupted hemidesmosome ultrastructure in patient skin biopsies. Proteasomal and lysosomal inhibition assays confirm proteolytic degradation of mutant α6 chains, establishing loss-of-function as the pathogenic mechanism ([PMID:9185503], [PMID:14675179]).

No conflicting evidence has been reported. Over two decades of independent genetic and experimental data affirm a definitive ITGA6–PA-JEB relationship with concordant inheritance, segregation, and functional concordance.

Clinical genetic testing of ITGA6 should be included in diagnostic and prenatal workflows for neonates and fetuses with suspected PA-JEB, enabling accurate recurrence risk assessment and informed genetic counseling.

References

• The Journal of clinical investigation • 1997 • A homozygous mutation in the integrin alpha6 gene in junctional epidermolysis bullosa with pyloric atresia. PMID:9185503
• Human molecular genetics • 1997 • Homozygous alpha6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia. PMID:9158140
• The Journal of investigative dermatology • 2003 • Rapid decay of alpha6 integrin caused by a mis-sense mutation in the propeller domain results in severe junctional epidermolysis bullosa with pyloric atresia. PMID:14675179
• Prenatal diagnosis • 2000 • Prenatal diagnosis of pyloric atresia-junctional epidermolysis bullosa syndrome in a fetus not known to be at risk. PMID:10701857
• The Journal of dermatology • 2017 • Compound heterozygosity for novel splice site mutations of ITGA6 in lethal junctional epidermolysis bullosa with pyloric atresia. PMID:27607025

Evidence Based Scoring (AI generated)