The clinical spectrum of leukocyte adhesion deficiency (LAD) III due to defective CalDAG-GEF1
ABSTRACT Leukocyte adhesion deficiency (LAD) type III is a rare syndrome characterized by severe recurrent infections, leukocytosis, and increased bleeding tendency. All integrins are normally expressed yet a defect in their activation leads to the observed clinical manifestations.
Less than 20 patients have been reported world wide and the primary genetic defect was identified in some of them. Here we describe the clinical features of patients in whom a mutation in the calcium and diacylglycerol-regulated guanine nucleotide exchange factor 1 (CalDAG GEF1) was found and compare them to other cases of LAD III and to animal models harboring a mutation in the CalDAG GEF1 gene.
The hallmarks of the syndrome are recurrent infections accompanied by severe bleeding episodes distinguished by osteopetrosis like bone abnormalities and neurodevelopmental defects.
- SourceAvailable from: Michael W. Hess
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- "Several LAD-III patients have displayed increased bone mineral density (Kilic and Etzioni, 2009; Malinin et al., 2009; McDowall et al., 2010; Sabnis et al., 2010), which points to the possibility that kindlin-3 plays a role in bone homeostasis. "
ABSTRACT: The blood cell-specific kindlin-3 protein is required to activate leukocyte and platelet integrins. In line with this function, mutations in the KINDLIN-3 gene in man cause immunodeficiency and severe bleeding. Some patients also suffer from osteopetrosis, but the underlying mechanism leading to abnormal bone turnover is unknown. Here we show that kindlin-3-deficient mice develop severe osteopetrosis because of profound adhesion and spreading defects in bone-resorbing osteoclasts. Mechanistically, loss of kindlin-3 impairs the activation of β1, β2, and β3 integrin classes expressed on osteoclasts, which in turn abrogates the formation of podosomes and sealing zones required for bone resorption. In agreement with these findings, genetic ablation of all integrin classes abolishes the development of podosomes, mimicking kindlin-3 deficiency. Although loss of single integrin classes gives rise to podosomes, their resorptive activity is impaired. These findings show that osteoclasts require their entire integrin repertoire to be regulated by kindlin-3 to orchestrate bone homeostasis.The Journal of Cell Biology 02/2011; 192(5):883-97. DOI:10.1083/jcb.201007141 · 9.83 Impact Factor
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- "Bleeding can be the presenting symptom and results in an ongoing requirement for red cell and platelet transfusions ( Kuijpers et al , 1997 ) . Hepatosplenomegally , possibly resulting from extra - medullary haematopoiesis , and an increase in bone density resembling osteopetrosis have also been reported ( Kuijpers et al , 2007 ; Kilic & Etzioni , 2009 ) . Patients have normal b 1 , b 2 and b 3 - integrin expression , but defective integrin activation through ' inside - out ' signalling pathways , which results in failure to establish high affinity ligand binding ( McDowall et al , 2003 ; Kinashi et al , 2004 ) . "
ABSTRACT: Neutrophils are amongst the first immune cells to arrive at sites of infection and play an important role as the host's first line of defence against invading pathogens. Defects of neutrophil number or function are usually recognized clinically by recurrent infections that often are life-threatening. Over the last few years, a number of genetic mutations have been discovered to be the basis for congenital neutropenia, adding to our understanding of the molecular basis of these diseases. While many genetic mutations that cause severe congenital neutropenia result in a differentiation block at the promyelocyte stage, defects of neutrophil function are more heterogeneous on clinical, genetic and mechanistic levels. In this review we discuss recent advances in our understanding of the genetic and molecular basis of human neutrophil disorders.British Journal of Haematology 11/2010; 151(4):312-26. DOI:10.1111/j.1365-2141.2010.08361.x · 4.71 Impact Factor
- "The presence of severe immunodeficiency with ectodermal changes is observed in X-linked osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia and immunodeficiency (OLEDAID). Common variable immune deficiency (CVID) has been described in association with a particular subtype of osteoclast-poor ARO , and some patients with leukocyte adhesion deficiency syndrome (LAD-III) also suffer from severe osteopetrosis [13,14]. "
Article: Osteopetrosis[Show abstract] [Hide abstract]
ABSTRACT: Osteopetrosis ("marble bone disease") is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. The overall incidence of these conditions is difficult to estimate but autosomal recessive osteopetrosis (ARO) has an incidence of 1 in 250,000 births, and autosomal dominant osteopetrosis (ADO) has an incidence of 1 in 20,000 births. Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or "malignant" ARO), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis). Classic ARO is characterised by fractures, short stature, compressive neuropathies, hypocalcaemia with attendant tetanic seizures, and life-threatening pancytopaenia. The presence of primary neurodegeneration, mental retardation, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO. Osteopetrosis is caused by failure of osteoclast development or function and mutations in at least 10 genes have been identified as causative in humans, accounting for 70% of all cases. These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable, and paves the way to understanding natural history, specific treatment where available, counselling regarding recurrence risks, and prenatal diagnosis in severe forms. Treatment of osteopetrotic conditions is largely symptomatic, although haematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure and currently offers the best chance of longer-term survival in this group. The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a complication of bone marrow suppression. Life expectancy in the adult onset forms is normal. It is anticipated that further understanding of the molecular pathogenesis of these conditions will reveal new targets for pharmacotherapy.Orphanet Journal of Rare Diseases 03/2009; 4(1, article 5):5. DOI:10.1186/1750-1172-4-5 · 3.36 Impact Factor