Leukocyte adhesion deficiency-3 (LAD3), also known as LAD1 variant (LAD1V), is an autosomal recessive disorder characterized by LAD1 (116920)-like immune deficiency and Glanzmann thrombasthenia (GT; 273800)-like bleeding problems. LAD3 results from mutations in FERMT3, or KINDLIN3, which encodes ... Leukocyte adhesion deficiency-3 (LAD3), also known as LAD1 variant (LAD1V), is an autosomal recessive disorder characterized by LAD1 (116920)-like immune deficiency and Glanzmann thrombasthenia (GT; 273800)-like bleeding problems. LAD3 results from mutations in FERMT3, or KINDLIN3, which encodes an intracellular protein that interacts with beta-integrins in hematopoietic cells. In LAD3, the adhesive functions of integrins on both leukocytes and platelets are disrupted, most likely due to defects in activation-dependent alterations of surface integrins that enable high-avidity binding to ligands on target cells, a process termed 'inside-out signaling' (Svensson et al., 2009; Zimmerman, 2009).
Kuijpers et al. (1997) reported a male infant, born of consanguineous Turkish parents, who developed recurrent bouts of nonpussing inflammatory lesions and bacterial infections. Wound healing was delayed, and the umbilical cord detached spontaneously at 5 weeks. By ... Kuijpers et al. (1997) reported a male infant, born of consanguineous Turkish parents, who developed recurrent bouts of nonpussing inflammatory lesions and bacterial infections. Wound healing was delayed, and the umbilical cord detached spontaneously at 5 weeks. By age 2 years, he developed a bleeding tendency in the presence of normal platelet numbers. Laboratory studies showed defective neutrophil activation and adhesion with normal expression of CD11 (see 153370)/CD18 (ITGB2; 600065), thus excluding a diagnosis of LAD1. However, the patient's leukocytes were deficient in beta-2-mediated adhesion ligand binding upon stimulation. Alon et al. (2003) reported an Arab child, born of consanguineous parents, who developed periumbilical cellulitis and Staphylococcal septicemia at age 5 days. The umbilical cord was shed at 4 weeks. Initial laboratory tests showed low hemoglobin, slightly reduced platelet count, and leukocytosis. During the subsequent months, he developed severe mucosal bleeding that necessitated blood and platelet transfusions, as well as recurrent nonsuppurating skin infections. Platelet aggregation studies demonstrated a grossly abnormal response to agonists. He died at age 6 years from a disseminated fungal infection after a mismatched bone marrow transplantation. A younger brother who presented with the same clinical and hematologic phenotypes at birth died at 1 week of age from sepsis. Laboratory studies showed an impaired ability of neutrophil and lymphocyte beta-1 (ITGB1; 135630) and beta-2 integrins to generate high avidity to their endothelial ligands and arrest cells on vascular endothelium in response to endothelial chemoattractant signals, despite normal expression and intrinsic function of integrins and chemokine receptors. The findings suggested a primary defect in integrin rearrangement at ligand-bearing contacts. In a patient with features of Glanzmann thrombasthenia and LAD1, McDowall et al. (2003) identified a form of integrin dysfunction involving ITGB1, ITGB2, and ITGB3 (173470). ITGB2 and ITGB3 were constitutively clustered. Although all 3 integrins were expressed on the cell surface at normal levels and were capable of function following extracellular stimulation, they could not be activated via the inside-out signaling pathways. Kuijpers et al. (2007) reported 9 patients with LAD1V from 7 unrelated consanguineous families from central Turkey, including the patient reported by Kuijpers et al. (1997). Patients presented in infancy with recurrent infections and/or bleeding, including skin infections, omphalitis, sepsis, petechiae, nose bleeds, anemia, and mucosal bleeding. Perianal abscesses were common. Infections were mainly bacterial and fungal. Wound healing was poor, and there was a moderate to severe bleeding tendency necessitating multiple red blood cell and platelet transfusions. Most patients also had hepatosplenomegaly. Laboratory studies indicated defective neutrophil adhesion, chemotaxis, and NADPH oxidase activity. Malinin et al. (2009) described 2 sibs, a boy and a girl, from the United Arab Emirates who developed severe bleeding and recurrent infections at 2 weeks of age, in spite of having normal platelet counts, hemoglobin levels, and peripheral blood cell morphology. An older brother and other family members lacked any history of recurrent bleeding or infections. Both patients also developed osteopetrosis at about 5 months of age. Malinin et al. (2009) noted that the symptoms were consistent with, but more severe, than those of patients previously reported with LAD3. Immortalized lymphocyte cell lines isolated from the 2 patients showed integrin activation defects. Bone marrow transplantation successfully resolved the clinical problems of both patients. Malinin et al. (2009) proposed the designation 'integrin activation deficiency disease' to reflect the defect underlying the symptoms. McDowall et al. (2010) reported an 11-month-old African American girl with a severe bleeding tendency from birth, recurrent bacterial infections, and osteopetrosis. Laboratory studies of patient cells showed normal expression of major T-cell integrins, but T cells failed to firmly adhere to ICAM1 (147840) and fibronectin (FN1; 135600) when adhesion was stimulated by inside-out signaling agonists. Activation of integrins from outside the cell showed that the integrins from patient T cells were capable of normal adhesion. The T cells from the mother adhered to and spread on ICAM1 normally, but patient T cells were unable to spread. The girl was successfully treated with bone marrow transplantation. Robert et al. (2011) described a 33-month-old first son of consanguineous Gypsy parents with LAD3 syndrome characterized by a serious bleeding defect and immune deficiency. The boy's height and neuropsychologic development were normal, and he was homozygous for a splice-site mutation in the FERMT3 gene (607901.0009). Analysis of leukocyte adhesion defects in the patient showed that initial bond formation was readily stimulated when neutrophils were exposed to bacterial fMLF or when neutrophils or lymphocytes were stimulated with a phorbol ester (PMA) or Mn(2+). However, attachment strengthening was defective in lymphocytes treated with PMA or Mn(2+) and in neutrophils stimulated with fMLF, whereas neutrophils responded normally to PMA or Mn(2+). The patient's T cells displayed defective integrin-mediated spreading and moderately decreased spreading on anti-CD3-coated surfaces. Integrin-mediated spreading in neutrophils was severely defective after incubation with fMLF or PMA, but not Mn(2+). Robert et al. (2011) concluded that the consequences of FERMT3 deficiency on beta-2 integrin function depend on both cell type and the stimulus used for integrin activation.
Svensson et al. (2009) noted that Pasvolsky et al. (2007) reported a C-to-A change at a putative splice acceptor site for exon 16 of the RASGRP2 gene (605577) as the cause of LAD3 in 2 Turkish patients. Svensson ... Svensson et al. (2009) noted that Pasvolsky et al. (2007) reported a C-to-A change at a putative splice acceptor site for exon 16 of the RASGRP2 gene (605577) as the cause of LAD3 in 2 Turkish patients. Svensson et al. (2009) identified this RASGRP2 change in 2 additional Turkish LAD3 patients, but a third Maltese LAD3 patient lacked any changes in the RASGRP2 gene. Furthermore, Svensson et al. (2009) showed that the C-to-A change had little or no effect on RASGRP2 mRNA and protein levels, and that RASGRP2 function could not be restored by expression of wildtype RASGRP2. Instead, Svensson et al. (2009) identified mutations in the KINDLIN3 gene as the cause of LAD3 in the 2 Turkish patients and the Maltese patient they reported. The Turkish patients were homozygous for an arg509-to-ter (R509X; 607901.0001) nonsense mutation, and the Maltese patient was homozygous for an A-to-G transition at the splice acceptor site of exon 14 (607901.0002). RT-PCR analyses showed that both mutations destabilized KINDLIN3 mRNA upstream of the mutations. Western blot analysis showed no expression of KINDLIN3 protein in the patients, whereas expression was normal in their parents. Interference reflection microscopy revealed that wildtype KINDLIN3 corrected defective adhesion to and migration on ICAM1 (147840) by patient B cells. Svensson et al. (2009) concluded that mutations in KINDLIN3 cause LAD3, and that wildtype KINDLIN3 can overcome LAD3 defects by generating integrin adhesive contacts and integrin-mediated migration of LAD3 lymphocytes. In the 2 sibs they reported with symptoms consistent with a severe form of LAD3, Malinin et al. (2009) identified a trp16-to-ter (W16X; 607901.0003) nonsense mutation in the KINDLIN3 gene. In 9 patients with LAD1V from 7 unrelated consanguineous families from central Turkey reported by Kuijpers et al. (2007), Kuijpers et al. (2009) identified 3 disease-associated variants in genes on chromosome 11q13: a splice site mutation in RASGRP2, an intronic deletion in NRXN2 (600566), and the R509X mutation in FERMT3. Two other patients, one from a consanguineous family from southeastern Turkey and the other from a consanguineous Arabic family, had novel nonsense mutations in FERMT3, but they lacked variants in RASGRP2 and NRXN2. The novel FERMT3 mutations were arg573 to ter (R573X; 607901.0004) in the Turkish patient and trp229 to ter (W229X; 607901.0005) in the Arabic patient. FERMT3 protein expression was undetectable in leukocytes and platelets of all patients tested, and all patients had similar neutrophil and platelet defects. Kuijpers et al. (2009) concluded that the silent RASGRP1 mutation a fnd the NRXN2 intronic deletion are not disease causing, but are in linkage disequilibrium with the nonsense mutation in exon 12 of the FERMT3 gene in the 7 previously reported Turkish families with LAD1V. They noted that variation in the clinical symptoms of the 11 LAD1V patients suggests that there is no strict genotype-phenotype relationship in LAD1V. In an African American girl with severe LAD3, McDowall et al. (2010) identified 2 different homozygous mutations in the FERMT3 gene: G308R (607901.0007) and 1275delT (607901.0008). In vitro studies indicated that the truncated protein could not restore either leukocyte adhesion or migration, whereas the G308R-mutant protein affected only migration. The patient's unaffected mother was heterozygous for both mutations, and showed about half-levels of FERMT3 mRNA, consistent with the lack of a functional gene on 1 allele. In a 33-month-old first son of consanguineous Gypsy parents with LAD3 syndrome, Robert et al. (2011) identified a homozygous splice-site mutation in the FERMT3 gene (607901.0009). His parents were heterozygous carriers. The patient and his unaffected mother were also heterozygous for a mutation in the ITGA2B gene (607759.0008).