Genetic analysis of integrin function in man: LAD-1 and other syndromes

The integrins are cell membrane receptors composed of alpha and beta subunits which orchestrate adhesive events in all tissues of the body (Hynes, R.O., 1992. Integrins: versatility, modulation, and signalling in cell adhesion. Cell 69, 11-25; and Hynes, R.O., 1999. Cell adhesion: old and new questions. Trends Cell Biol. 9, M33-37). At present 18 alpha subunits and 8 beta subunits have been identified which are loosely organised into families. There are three inherited autosomal recessive diseases in man which involve germline mutations in genes coding for integrins. Leukocyte adhesion deficiency-1 (LAD-1) is the result of mutations in the beta2 subunit of the CD11/CD18 integrins, LFA-1, Mac-1, p150,95 and alphadbeta2. The bleeding disorder Glanzmann thrombasthenia is caused by mutations in either the alpha or beta subunit of the platelet integrin, alphaIIbbeta3. Thirdly, it is now recognised than one of the variants of the usually lethal skin blistering disorder, epidermolysis bullosa (JEB-PA), is caused by mutation in either the alpha or beta subunit of the epithelial hemidesmosome integrin, alpha6beta4. Many of the mutations cause defective alphabeta heterodimer formation. The majority of the beta subunit mutations are in the conserved N-terminal region known as the betaI domain. It is suggested that this region participates in alphabeta heterodimer formation.