TY - JOUR
T1 - LAD-1/variant syndrome is caused by mutations in FERMT3
AU - Kuijpers, Taco W
AU - van de Vijver, Edith
AU - Weterman, Marian A J
AU - de Boer, Martin
AU - Tool, Anton T J
AU - van den Berg, Timo K
AU - Moser, Markus
AU - Jakobs, Marja E
AU - Seeger, Karl
AU - Sanal, Ozden
AU - Unal, Sule
AU - Cetin, Mualla
AU - Roos, Dirk
AU - Verhoeven, Arthur J
AU - Baas, Frank
PY - 2009/5/7
Y1 - 2009/5/7
N2 - 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.
AB - 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.
KW - Antineoplastic Combined Chemotherapy Protocols/metabolism
KW - Blotting, Western
KW - Chromosome Mapping
KW - Cisplatin/metabolism
KW - Codon, Nonsense/genetics
KW - Cyclophosphamide/metabolism
KW - DNA Primers/chemistry
KW - Doxorubicin/metabolism
KW - Guanine Nucleotide Exchange Factors/genetics
KW - Homozygote
KW - Humans
KW - Leukocyte-Adhesion Deficiency Syndrome/genetics
KW - Membrane Proteins/genetics
KW - Neoplasm Proteins/genetics
KW - Nerve Tissue Proteins/genetics
KW - Platelet Activation
KW - Polymorphism, Single Nucleotide/genetics
KW - RNA Splicing
U2 - 10.1182/blood-2008-10-182154
DO - 10.1182/blood-2008-10-182154
M3 - Article
C2 - 19064721
VL - 113
SP - 4740
EP - 4746
JO - Blood
JF - Blood
SN - 0006-4971
IS - 19
ER -