LAD-I/variant syndrome is caused by mutations in FERMT

摘要

Leukocyte adhesion deficiency- /variant (LADv) syndrome presents early in life and manifests by infections without pus formation in the presence of a leukocytosis combined with a Glanzmann-type bleeding disorder, resulting from a hematopoietic defect in integrin activation. In 7 consanguineous families, we previously established that this defect was not the result of defective Rap activation, as proposed by other investigators. In search of the genetic defect, we carried out homozygosity mapping in ofthese patients, and a -Mb region on chromosome was identified. All 7 LADv families share the same haplotype, in which disease-associated sequence variants were identified: a putative splice site mutation in CALDAGGEF (encoding an exchange factor for Rap), an intronic .8-kb deletion in NRXN, and a premature stop codon (p.Arg09X) in FERMT. Two other LAD v patients were found to carry different stop codons in FERMT (p.Arg7X and p.Trp9X) and lacked the CALDAGGEFand NRXN mutations, providing convincing evidence that FERMT is the gene responsible for LADv. FERMT encodes kindlin- in hematopoietic cells, a protein present together with integrins in focal adhesions. Kindlin- protein expression was undetectable in the leukocytes and platelets of all patients tested. These results indicate that the LADv syndrome is caused by truncating mutations in FERMT.