title: LAD-1/variant syndrome is caused by mutations in FERMT3.
abstract: Leukocyte adhesion deficiency-1/variant (LAD1v) 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 Rap1 activation, as proposed by other investigators. In search of the genetic defect, we carried out homozygosity mapping in 3 of these patients, and a 13-Mb region on chromosome 11 was identified. All 7 LAD1v families share the same haplotype, in which 3 disease-associated sequence variants were identified: a putative splice site mutation in CALDAGGEF1 (encoding an exchange factor for Rap1), an intronic 1.8-kb deletion in NRXN2, and a premature stop codon (p.Arg509X) in FERMT3. Two other LAD1v patients were found to carry different stop codons in FERMT3 (p.Arg573X and p.Trp229X) and lacked the CALDAGGEF1 and NRXN2 mutations, providing convincing evidence that FERMT3 is the gene responsible for LAD1v. FERMT3 encodes kindlin-3 in hematopoietic cells, a protein present together with integrins in focal adhesions. Kindlin-3 protein expression was undetectable in the leukocytes and platelets of all patients tested. These results indicate that the LAD1v syndrome is caused by truncating mutations in FERMT3.
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands. t.w.kuijpers@amc.uva.nl
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.forename: Edith
authors.initials: E
authors.lastname: van de Vijver
authors.forename: Marian A J
authors.initials: MA
authors.lastname: Weterman
authors.forename: Martin
authors.initials: M
authors.lastname: de Boer
authors.forename: Anton T J
authors.initials: AT
authors.lastname: Tool
authors.forename: Timo K
authors.initials: TK
authors.lastname: van den Berg
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.forename: Marja E
authors.initials: ME
authors.lastname: Jakobs
authors.forename: Karl
authors.initials: K
authors.lastname: Seeger
authors.forename: Ozden
authors.initials: O
authors.lastname: Sanal
authors.forename: Sule
authors.initials: S
authors.lastname: Unal
authors.forename: Mualla
authors.initials: M
authors.lastname: Cetin
authors.forename: Dirk
authors.initials: D
authors.lastname: Roos
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Verhoeven
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism; D015153:Blotting, Western; D002874:Chromosome Mapping; D002945:Cisplatin / Q000378:metabolism; D018389:Codon, Nonsense / Q000235:genetics*; D003520:Cyclophosphamide / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004317:Doxorubicin / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006720:Homozygote; D006801:Humans; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D015539:Platelet Activation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012326:RNA Splicing
chemical_list: D018389:Codon, Nonsense; D017931:DNA Primers; C477322:FERMT3 protein, human; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C415483:RASGRP2 protein, human; C093175:neurexin II; D004317:Doxorubicin; D003520:Cyclophosphamide; D002945:Cisplatin