A homozygous mutation in the integrin alpha6 gene in junctional epidermolysis bullosa with pyloric atresia.

Abstract

The ␣ 6 integrin subunit participates in the formation of both ␣ 6 ␤ 1 and ␣ 6 ␤ 4 laminin receptors, which have been reported to play an important role in cell adhesion and migration and in morphogenesis. In squamous epithelia, the ␣ 6 ␤ 4 heterodimer is the crucial component for the assembly and stability of hemidesmosomes. These anchoring structures are ultrastructurally abnormal in patients affected with junctional epidermolysis bullosa with pyloric atresia (PA-JEB), a recessively inherited blistering disease of skin and mucosae characterized by an altered immunoreactivity with antibodies specific to integrin ␣ 6 ␤ 4. In this report, we describe the first mutation in the ␣ 6 integrin gene in a PA-JEB patient presenting with generalized skin blistering, aplasia cutis, and defective expression of integrin ␣ 6 ␤ 4. The mutation (791delC) is a homozygous deletion of a single base (C) leading to a frameshift and a premature termination codon that results in a complete absence of ␣ 6 polypeptide. We also describe the DNA-based prenatal exclusion of the disease in this family at risk for recurrence of PA-JEB. Our results demonstrate that, despite the widespread distribution of the ␣ 6 integrin subunit, lack of expression of the ␣ 6 integrin chain is compatible with fetal development, and results in a phenotype indistinguishable from that caused by mutations in the ␤ 4 chain, which is expressed in a more limited number of tissues. ( J. Clin. Invest. 1997. 99:2826-2831.)

Integrin Regulation of Epidermal Functions in Wounds

“…Indeed, the essential adhesion role for a 6 b 4 in hemidesmosomes is revealed by the extensive epidermal blistering that occurs in mice that harbor a null mutation in either the Itga6 or Itgb4 gene (encoding the a 6 or b 4 subunit, respectively), [65][66][67] and in human patients with loss-of-function mutations in a 6 b 4 . 68,69 In contrast, the absence of a 3 b 1 (through null, or loss-of-function, mutation of the Itga3 gene encoding the a 3 subunit) causes much less severe epidermal blistering in newborn mice 50 or young patients, 70 and hemidesmosomes are left intact in non-blistered regions of a 3 b 1 -deficient skin. Moreover, blisters in a 3 b 1 -deficient skin form via a mechanism of BM rupture that is distinct from loss of epidermal attachment to laminin-332 per se, which persists in these mice via a 6 b 4 .…”

Gene Correction of Integrin β4-dependent Pyloric Atresia-Junctional Epidermolysis Bullosa Keratinocytes Establishes a Role for β4 Tyrosines 1422 and 1440 in Hemidesmosome Assembly

“…The crucial importance of the interaction between laminin-5 and its ␣ 6 ␤ 4 receptor in maintaining the integrity of the integument has been unambiguously proven by the generation of ␣ 6 -and ␤ 4 -null mice (10 -12) and by the identification of gene mutations in patients suffering from a devastating blistering disorder of the skin known as junctional epidermolysis bullosa (JEB). In most cases, JEB is due to mutations in LAMA3, LAMB3, and LAMC2 genes (13-15) and in ITGA6 and ITGB4 genes, which encode ␣ 6 and ␤ 4 integrin subunits, respectively (16,17). Mutations in ITGA6 and ITGB4 are usually associated to pyloric atresia (PA)-JEB (16,17).…”

“…In most cases, JEB is due to mutations in LAMA3, LAMB3, and LAMC2 genes (13-15) and in ITGA6 and ITGB4 genes, which encode ␣ 6 and ␤ 4 integrin subunits, respectively (16,17). Mutations in ITGA6 and ITGB4 are usually associated to pyloric atresia (PA)-JEB (16,17).…”

“…In most cases, JEB is due to mutations in LAMA3, LAMB3, and LAMC2 genes (13-15) and in ITGA6 and ITGB4 genes, which encode ␣ 6 and ␤ 4 integrin subunits, respectively (16,17). Mutations in ITGA6 and ITGB4 are usually associated to pyloric atresia (PA)-JEB (16,17).The cytoplasmic domain of ␣ 6 ␤ 4 contains two pairs of type III fibronectin (FN)-like repeats separated by a 142-amino acid connecting segment (CS). This CS is the target of multiple regulatory mechanisms, including tyrosine phosphorylation (18) and proteolytic processing (19).…”

Les tétraspanines dans la physiopathologie de la peau

“…Cette mutation conduit à une forme tronquée de CD151 qui ne présente plus de domaine pouvant s'associer avec les intégrines α3β1 et α6β1. De façon intéressante, une mutation de la sous-unité α6 de l'intégrine partenaire entraîne également ce type d'affection cutanée [19], ce qui suggère que les altérations touchant l'interaction entre CD151 et les intégrines sont essentielles dans le développement de cette pathologie cutanée. L'ensemble de ces données montre donc un rôle des tétraspanines CD9, CD81 et CD151 dans l'adhérence des kératinocytes entre eux et à la matrice, mais également dans leur motilité.…”