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Review
. 2012 Jan 15;48(1):53-61.
doi: 10.1016/j.bcmd.2011.10.004. Epub 2011 Nov 30.

Hematologically important mutations: leukocyte adhesion deficiency (first update)

Edith van de Vijver  1 , Anne Maddalena, Özden Sanal, Steven M Holland, Gulbu Uzel, Manisha Madkaikar, Martin de Boer, Karin van Leeuwen, M Yavuz Köker, Nima Parvaneh, Alain Fischer, S K Alex Law, Nigel Klein, F Ilhan Tezcan, Ekrem Unal, Turkan Patiroglu, Bernd H Belohradsky, Klaus Schwartz, Raz Somech, Taco W Kuijpers, Dirk Roos
Affiliations
Review

Hematologically important mutations: leukocyte adhesion deficiency (first update)

Edith van de Vijver et al. Blood Cells Mol Dis. .

Abstract

Leukocyte adhesion deficiency (LAD) is an immunodeficiency caused by defects in the adhesion of leukocytes (especially neutrophils) to the blood vessel wall. As a result, patients with LAD suffer from severe bacterial infections and impaired wound healing, accompanied by neutrophilia. In LAD-I, mutations are found in ITGB2, the gene that encodes the β subunit of the β(2) integrins. This syndrome is characterized directly after birth by delayed separation of the umbilical cord. In the rare LAD-II disease, the fucosylation of selectin ligands is disturbed, caused by mutations in SLC35C1, the gene that encodes a GDP-fucose transporter of the Golgi system. LAD-II patients lack the H and Lewis Le(a) and Le(b) blood group antigens. Finally, in LAD-III (also called LAD-I/variant) the conformational activation of the hematopoietically expressed β integrins is disturbed, leading to leukocyte and platelet dysfunction. This last syndrome is caused by mutations in FERMT3, encoding the kindlin-3 protein in all blood cells that is involved in the regulation of β integrin conformation.

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Figures

Figure 1
Figure 1
Schematic overview of mutations in ITGB2. a. The number of mutated alleles, the type of mutation and their position along the exons of ITGB2, with active domains depicted in brown (see underneath fig. 1b). Symbols, explained on the right, represent mutated alleles. Numbers refer to nucleotides in cDNA. b. Domain structure of the β2 integrin (CD18) and the location of each mutation, with active domains depicted in yellow, green and blue. Protein interaction sites are shown for some domains. Symbols, explained on the right, represent separate mutations. Numbers refer to amino acids in β2 integrin. Figure drawn by Dr. M. Yavuz Köker.
Figure 2
Figure 2
Schematic overview of mutations in FERMT3. a. The number of mutated alleles, the type of mutation and their position along the exons of FERMT3, with active domains depicted in brown (see underneath fig. 2b). Symbols, explained on the right, represent mutated alleles. Numbers refer to nucleotides in cDNA. b. Domain structure of kindlin-3 and the location of each mutation, with active domains depicted in yellow, green and blue. Protein interaction sites are shown for some domains. Symbols, explained on the right, represent separate mutations. Numbers refer to amino acids in kindlin-3. Figure drawn by Dr. M. Yavuz Köker.
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