Bernard-Soulier Syndrome with Severe Bleeding: Absent Platelet Glycoprotein lb alpha Due to a Homozygous One-base Deletion

1996 ◽  
Vol 76 (05) ◽  
pp. 670-674 ◽  
Author(s):  
Chaoyang Li ◽  
Dominick N Pasquale ◽  
Gerald J Roth
Keyword(s):  
Stop Codon ◽  
Surface Membrane ◽  
Genetic Defect ◽  
Premature Stop Codon ◽  
Platelet Glycoprotein ◽  
Severe Bleeding ◽  
Giant Platelets ◽  
Platelet Disorder ◽  
Oligonucleotide Hybridization ◽  
Bernard Soulier Syndrome

SummaryBernard-Soulier syndrome is a rare congenital platelet disorder that affects a surface membrane adhesion receptor, glycoprotein (GP) Ib-V-IX. Both the genetic defects and the bleeding diatheses associated with the syndrome are heterogeneous due, in part, to the complexity of the involved receptor which consists of four different members, GPs: Ibα-Mr 143 K (contains the von Willebrand factor-binding site), Ibβ-Mr 22 K, V-Mr 83 K and IX-Mr 20 K. We studied a kindred that includes a 40 year-old man with severe Bernard-Soulier syndrome: life-threatening gastrointestinal bleeding, thrombocytopenia, giant platelets and absent ristocetin-dependent platelet aggregation. By Southern blotting, PCR amplification/sequencing, hetero-duplex analysis, and allele-specific oligonucleotide hybridization, the Ib-V-IX genes were analyzed, and the molecular genetic defect was defined as a one-base deletion in the GPIbα gene, involving an adenine of codon 19. The mutation, K19R, homozygous in the propositus and heterozygous in the available unaffected relatives, leads to a frame shift in codons 19-21 and a premature stop codon after codon 21. No functional GPIbα can be produced from the mutant allele, implying that the platelets of the affected patient lack all GPIbα. Within the spectrum of Bernard-Soulier syndrome, this patient’s disorder exemplifies a severe or “classic” extreme; an “experiment of Nature” that illustrates the effect of a complete deficiency of the ligand-binding chain (GPIbα) of the GPIb-V-IX receptor.

The genetic defect in two well-studied cases of Bernard-Soulier syndrome: a point mutation in the fifth leucine-rich repeat of platelet glycoprotein Ib alpha

Blood ◽  
1995 ◽  
Vol 86 (10) ◽  
pp. 3805-3814 ◽  
Author(s):  
C Li ◽  
SE Martin ◽  
GJ Roth
Keyword(s):  
Point Mutation ◽  
Genetic Defect ◽  
Pcr Amplification ◽  
Mutant Gene ◽  
Surface Expression ◽  
Platelet Glycoprotein ◽  
Molecular Defect ◽  
Wild Type ◽  
Giant Platelets ◽  
Bernard Soulier Syndrome

Bernard-Soulier syndrome (B-Ss) is a rare congenital bleeding disorder caused by abnormal giant platelets, thrombocytopenia, and defective glycoprotein (GP) Ib-V-IX, the adhesion receptor for von Willebrand factor (vWF). This report describes the molecular defect in two related individuals with well-established B-Ss whose platelets exhibit decreased GPIb-IX and normal GPV on their surfaces. The GPIb-V-IX genes of the two patients were analyzed by Southern blotting, hetero-duplex analysis, and polymerase chain reaction (PCR) amplification/sequencing. A point mutation was found in codon 129 of the GPIb alpha gene that results in the substitution of proline for leucine in the first position of the fifth leucine-rich glycoprotein repeat of the mature gene product. The mutation (CTC: leucine, wild-type to CCC: proline, mutant) eliminates a Sac I restriction site, facilitating analysis of the mutation in the propositi (both homozygotes), unaffected family members (8 heterozygotes and 8 wild-type), and 58 normal controls (116 wild-type alleles). The status of the genomes was confirmed by the sequencing of platelet cDNA. The mutation does not affect transcription of the Ib-IX genes, as estimated by PCR and Northern blot analysis, but it does inhibit surface expression of the receptor as assessed by transient transfection of mutant and wild-type GPIb alpha genes into mouse Ib beta-IX L cells. Many of the cells (43%) transfected with the normal gene express surface GPIb alpha, whereas untransfected cells and those transfected with the mutant gene lack surface GPIb alpha entirely. Patient platelets were tested both for vWF binding in the presence of ristocetin and for surface GPIb-IX expression. In these instances, despite their inability to agglutinate with ristocetin and vWF, patient platelets exhibit about 40% of normal vWF binding and 40% of normal Ib-IX surface antigens. The results suggest that the described mutation (GPIb alpha: Leu129 -> Pro) affects the conformation of the GPIb-V-IX receptor, alters its availability on platelet surfaces, and causes the observed Bernard-Soulier phenotype.

Abnormal Large Platelets Are Associated Not Only with von Willebrand Disease (VWD) Type 2B (Including Type 2B/1 New York) but Also with Severe Type 3: A Potential Role for von Willebrand Factor (VWF) in Megakaryocytopoiesis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 101-101 ◽  
Author(s):  
Paquita Nurden ◽  
Alan T. Nurden ◽  
Jocelyne Enouf ◽  
Silvia La Marca ◽  
Luciano Baronciani ◽  
...  
Keyword(s):  
Stop Codon ◽  
Premature Stop Codon ◽  
Von Willebrand Disease ◽  
Platelet Glycoprotein ◽  
Gene Gain ◽  
Giant Platelets ◽  
Immunogold Staining ◽  
Platelet Production ◽  
Large Deletions ◽  
Von Willebrand

Abstract Background: VWD type 2B results from mutations in exon 28 of the VWF gene. Gain of function of this adhesive protein results in an increased affinity for the platelet glycoprotein (GP) Ib-IX-V complex. Recently we reported that impaired megakaryocytopoiesis results from an abnormal interaction between GPIb with newly synthesized VWF in megakaryocytes of a family with the R1308P mutation (Blood2006; 108:2587–95). Aim of the Study: to further examine the potential consequences of VWF abnormalities on platelet production we have studied a series of patients with different types of VWD. Patients, Methods: 13 VWD patients were enrolled in the study after informed consent. Diagnoses of VWD were performed according to the criteria of the ISTH-SSC-SC. Included were 8 VWD 2B patients from 6 families with the following mutations: R1306W (n=1), R1308C (n=1), I1309V (n=1), V1326M (n=2), R1341Q (n=2) and P1266L (n=1, 2B/1NY). Also studied were 5 additional VWD cases characterized by low/absent VWF in their platelets: VWD 2M (n=1, D1277-E78delInsL), VWD 3 without inhibitors against VWF (n=2, 276delT/257delA and 6182delT/6182delT) and VWD with isoantibodies against VWF (n=2, large deletions of the VWF gene). The platelet count was decreased at the time of examination for 6/8 VWD 2B patients and normal for 2/8 (n=1 V1316M and n=1 P1266L). Platelet counts were normal in the remaining 5 patients with VWD types 3, and 2M. Electron microscopy (EM) of platelets and immunolocalization of VWF were performed. Results: EM showed the presence of an increased population of giant platelets (15 to 40% versus <10% for controls) in all VWD 2B. Characteristics of these platelets were the presence of large vacuoles often filled with material and the presence of numerous membrane complexes. Additional abnormalities were observed in the patient with 2B/1NY; alpha-granule morphology was different with a population of enlarged granules, sometimes giant. There was also a heterogeneneous distribution with some platelets almost devoid of alpha-granules. Immunogold staining for all type 2B patients showed that VWF was present not only inside the granules but also in the surface-connected canalicular system. For 3/8 patients with VWD 2B, cleaved caspase was present in the platelets indicating abnormal caspase activity at least for R1341Q and V1316M. In VWD 2M (mutation D1277-E78delInsL) characterized by low platelet VWF content as well as in the VWD 3 (n=2) with a premature stop codon, no significant modification of platelet morphology was found. Some residual VWF was also seen in the alpha-granules of these 2 VWD 3 patients. In contrast, a significant number of enlarged platelets with numerous vacuoles were found in the 2 VWD 3 with large deletions and isoantibodies directed against VWF. Immunogold labelling for platelet VWF was completely negative for these two patients. Conclusions: Patients with VWD types 2B and 3 (undetectable VWF) show platelet production defects of varying severity, suggesting a major role of VWF in the fine regulation of megakaryocytopoiesis. Up-regulation or loss of the interaction between VWF and GPIb may lead to a variable proportion of giant platelets with or without thrombocytopenia.

Identification of a Homozygous Single Base Pair Deletion in the Gene Coding for the Human Platelet Glycoprotein Ibα Causing Bernard-Soulier Syndrome

1994 ◽  
Vol 72 (03) ◽  
pp. 444-449 ◽  
Author(s):  
S Simsek ◽  
L G Admiraal ◽  
P W Modderman ◽  
C E van der Schoot ◽  
A E G Kr von dem Borne
Keyword(s):  
Restriction Enzyme ◽  
Genetic Basis ◽  
Molecular Genetic ◽  
Genetic Defect ◽  
Platelet Glycoprotein ◽  
Enzyme Analysis ◽  
Giant Platelets ◽  
Platelet Surface ◽  
Base Pair Deletion ◽  
Bernard Soulier Syndrome

SummaryBernard-Soulier Syndrome (BSS) is a hereditary bleeding disorder which is caused by the absence or the dysfunction of the platelet glycoprotein Ib/IX/V (GP Ib/IX/V) complex, the major receptor for von Willebrand factor (vWf). BSS is characterized by the presence of giant platelets that show a reduced binding of vWf. Although BSS is a well-characterized disease, and many cases have been described in the literature, the molecular genetic basis of this disorder has been studied in only a few patients.We have studied the genetic basis of the defect in a BSS patient. Flow cytometric analysis of the platelet membrane glycoproteins revealed a significant decrease or absence of GP Ibα on the platelet surface, and low levels of GP V and GP IX. In subsequent immunopre-cipitation experiments, we confirmed the presence of GP V (although in significantly decreased amounts) on the platelet surface. These results indicated a defect in the GP Ibα chainGenomic DNA coding for GP Ibα was amplified, using the polymerase chain reaction (PCR). Subsequent direct sequence analysis demonstrated a homozygous deletion of T317 resulting in a frameshift deletion and predicting a substitution of Arg for Leu76. This deletion causes a shift in the reading frame, predicting a premature stop codon after 19 altered amino-acids, leading to a severily truncated molecule. The molecular genetic defect found in this patient differed from the mutations observed in three other BSS patients described in the literature. This points to a marked hetereogeneity of this disease.The single basepair deletion created a target site for the restriction enzyme Hhal. This allowed us to perform PCR-ASRA (Allele-Specific Restriction enzyme Analysis) on all available family members. Both parents and the daughter of the patient appeared to be heterozygous for the deletion, while the homozygosity of the propositus for the mutant allele was confirmed.

scholarly journals Double heterozygosity for mutations in the platelet glycoprotein IX gene in three siblings with Bernard-Soulier syndrome

Blood ◽  
1993 ◽  
Vol 81 (9) ◽  
pp. 2339-2347 ◽  
Author(s):  
SD Wright ◽  
K Michaelides ◽  
DJ Johnson ◽  
NC West ◽  
EG Tuddenham
Keyword(s):  
Normal Subjects ◽  
Immunoblot Analysis ◽  
Platelet Glycoprotein ◽  
Bleeding Tendency ◽  
Missense Mutations ◽  
Coding Region ◽  
Giant Platelets ◽  
Double Heterozygosity ◽  
Induced Aggregation ◽  
Bernard Soulier Syndrome

Abstract Bernard-Soulier syndrome (BSS) giant platelets have defective and/or deficient glycoprotein (GP) Ib/IX complexes, causing absent ristocetin- induced aggregation, defective interaction with von Willebrand factor, morphologic abnormality, and a clinical bleeding tendency. Recently several mutations have been described in the platelet GPIb alpha gene in individuals exhibiting the BSS phenotype. We have studied a family with classical BSS, and have excluded lesions at the GPIb alpha locus by restriction fragment length polymorphism linkage analysis. Analysis of the genes for two other components of the platelet GPIb:IX complex, namely GPIb beta and GPIX, showed two different missense mutations in the coding region of the GPIX gene: an A-->G transition in codon 21 results in conversion of an aspartic acid to glycine and an A-->G change in codon 45 converts an asparagine residue to serine. Three affected individuals are doubly heterozygous for these mutations, which alter conserved residues in or flanking the GPIX leucine-rich glycoprotein motif. Both mutations create new recognition sites for the enzyme Fnu 4H1; therefore, this enzyme was used to screen 60 normal subjects (120 alleles). Neither mutation was detected in any subject other than direct relatives of the affected individuals. Although low levels of GPIb were demonstrable by both flow cytometry and immunoblot analysis in an affected individual's platelets, there was no evidence of GPIX immunoreactivity. We propose that expression of abnormal GPIX prevents stable assembly of the GPIb/IX complex, causing BSS in the doubly heterozygous individuals in this family.

BERNARD-SOULIER SYNDROME: WHOLE BLOOD DIAGNOSTIC ASSAYS OF PLATELETS

1987 ◽  
Author(s):  
W L Nichols ◽  
S E Kaese ◽  
D A Gastineau ◽  
L A Otteman ◽  
E J W Bowie
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Platelet Rich Plasma ◽  
Blood Platelet ◽  
Laboratory Diagnosis ◽  
Light Transmittance ◽  
Immunocytochemical Staining ◽  
Platelet Glycoprotein ◽  
Giant Platelets ◽  
Bernard Soulier Syndrome

Diagnosis of Bernard-Soulier syndrome (BSS) is complicated by the difficulty of separating the giant platelets from other blood cells to pursue analyses of platelet function and structure. We report on the utility of three whole blood assay techniques for diagnosis of a patient with BSS. To our knowledge, these three techniques have not been simultaneously applied or compared for efficacy in laboratory diagnosis of BSS. (1) Whole blood platelet aggregation responses, studied with an electrical impedence aggregometer, were equivalent to those more laboriously obtained using platelet-rich plasma prepared by unit gravity sedimentation, studied with an optical light transmittance aggregometer. Platelet aggregation responses were normal with ADP or collagen stimulation, and absent with Ristocetin or bovine plasma stimulation. (2) Whole blood radioimmunoassay of platelet glycoprotein (GP) expression was performed using iodinated murine monoclonal antibodies HP1-1D (anti-GP IIb/IIIa) and 6D1 (anti-GPlb, kindly supplied by Dr. Barry Coller, Stony Brook, NY). After incubation with citrated whole blood, centrifugation was used to separate cell-bound antibody which was quantitated with a gamma counter. The patient’s whole blood had a normal level of cell-bound GP Ilb/IIIa, but a markedly reduced level of cell-bound GP lb (5% of normal mean; n = 20). (3) Whole blood smear immunocytochemical staining with the monoclonals (indirect immuno-alkaline phosphatase technique), and qualitative analysis by light microscopy, revealed a marked reduction of GP lb expression by the patient’s giant platelets, whereas GP Ilb/IIIa expression was normal. This latter technique might be especially valuable as a screening technique when the patient is not directly available for laboratory study. Together with the patient’s life-long history of thrombocytopenia and moderate bleeding diathesis, and other laboratory observations including markedly prolonged bleeding times and reduced whole blood prothrombin consumption, these data established diagnosis of BSS. We conclude that these three relatively simple assays of platelets in whole blood should be of particular value in the laboratory differential diagnosis of patients with congenital thrombocytopenias and giant platelet syndromes.

scholarly journals Giant (Bernard-Soulier) Platelets are Normal Sized in Circulation

1977 ◽  
Author(s):  
M. M. Frojmovic ◽  
John G. Milton ◽  
J. P. Caen
Keyword(s):  
Blood Smear ◽  
Abnormal Behaviour ◽  
Giant Platelets ◽  
Normal Platelet ◽  
Blood Smears ◽  
Platelet Disorder ◽  
Mean Diameter ◽  
Giant Size ◽  
Peripheral Blood Smears ◽  
Bernard Soulier Syndrome

Bernard-Soulier Syndrome (BSS) is a platelet disorder for which one of the characteristics is the appearance of “giant” platelets on peripheral blood smears. A comparison is made between the shape distributions of platelets obtained from normal (9) and BSS (3) donors. Geometric parameters are evaluated from a cinematographic analysis of freely rotating glutaraldehyde-hardened and unfixed platelets and of platelets on blood smear. On blood smear, normal platelets have a mean diameter of 1.8 ± 0.2 μm, where 10% have a diameter greater than 2.5μm (Weiss, et al (1974). Am. J. Med. 57: 920). On the other hand, BSS platelets are significantly larger, having a mean diameter of 3.3 + 0.7/μm, with 80% having a diameter greater than 2.5μm. These observations are consistent with all published reports concerning BSS platelets and suggest donors homozygous for this disorder (Bithell, et al (1972) N. Y. Acad. Sei. 201: 145). In contrast, the freely circulating disc-form of the BSS platelet is essentially indistinguishable from a normal platelet: mean diameter and thickness of 3.2 ± 0.3μm, and 1.4 ± 0.4 μm respectively, as compared with 3.2 ± 0.3 μm and 1.1 ± 0.4 μm for normal platelets.It is concluded that the giant size of BSS platelets results from abnormal behaviour of these platelets during the preparation of the blood smear.

Heterogenous Expression of Glycoprotein lb, IX and V in Platelets from Two Patients with Bernard-Soulier Syndrome Caused by Different Genetic Abnormalities

1995 ◽  
Vol 74 (06) ◽  
pp. 1411-1415 ◽  
Author(s):  
Masaaki Noda ◽  
Kingo Fujimura ◽  
Toshiro Takafuta ◽  
Takeshi Shimomura ◽  
Tetsuro Fujlmoto ◽  
...  
Keyword(s):  
Complex Analysis ◽  
Transmembrane Domain ◽  
Stop Codon ◽  
Expression Patterns ◽  
Premature Stop Codon ◽  
Surface Expression ◽  
Coding Region ◽  
Genetic Changes ◽  
Pcr Products ◽  
Bernard Soulier Syndrome

SummaryBernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder, which is caused by deficiency or decrease of the platelet GPIb/IX/V complex. Analysis of two patients with BSS by How cytometry of the blood revealed different expression patterns of the components of the GPIb/IX/V complex. In case 1, GPIX was completely absent but residual amounts of GPIbα and GPV were detectable; in case 2, GPIbα was completely absent. We amplified the coding regions of GPIbα, GPIbß, GPV, and GPIX from the patients’ genomic DNA with the polymerase chain reaction (PCR) and sequenced the PCR products. In case 1, we identified a point mutation in the GPIX coding region that changes the codon for tryptophan-126 (TGG) to a nonsense codon (TGA). In case 2, we found a deletion of nucleotide within seven adenine repeats at the position of 1932 to 1938 in the coding region of GPIbα, which causes a frame shift that results in 58 altered amino acids and a premature stop codon. These genetic changes alter the transmembrane domain of GPIX or GPIbα and, therefore, would prevent proper insertion of the proteins in the plasma membrane. Thus, abnormality of a single component protein (GPIX or GPIbα) alters the assembly of the GPIb/IX/V complex and causes heterogenous surface expression of GPIbα, GPV and GPIX.

Compound Heterozygosity (554-589 del, C515-T Transition) in the Platelet Glycoprotein Ibα Gene in a Patient with a Severe Bleeding Tendency

1999 ◽  
Vol 81 (04) ◽  
pp. 486-492 ◽  
Author(s):  
Maurizio Margaglione ◽  
Giovanna D’Andrea ◽  
Elvira Grandone ◽  
Vincenzo Brancaccio ◽  
Aldo Amoriello ◽  
...  
Keyword(s):  
Flow Cytometric Analysis ◽  
Normal Function ◽  
Platelet Glycoprotein ◽  
Severe Bleeding ◽  
Bleeding Tendency ◽  
Giant Platelets ◽  
Novel Variant ◽  
Leucine Rich Repeats ◽  
Von Willebrand

SummaryGiant platelets in the blood smear, absent in vitro platelet agglutination in response to ristocetin, and normal aggregation, ATP secretion and thromboxane B2 formation were found in a young patient with a life-long bleeding tendency. Ristocetin-induced von Willebrand factor binding to her platelets was less than 10% of normal. Flow cytometric analysis with monoclonal antibodies LJ-Ib-1, LJ-Ib-10, and LJ-P3 was consistent with the latter finding. SDS-PAGE analysis of solubilized platelets showed a marked reduction of the platelet glycoprotein (GP) Ibα. Genetic characterisation demonstrated that the patient and her father were heterozygous for a deletion of 36 nucleotides (positions 554-589) leading to a mutant GPIbμ (deletion of aminoacids from residue 169 to 180 and a Glu → Lys substitution at residue 181). In addition, a C → T transition at nucleotide 515 in the other allele of the GPIbα gene was found in the patient and in her mother that results in the substitution of alanine for valine in codon 156 (Bernard-Soulier type Bolzano). These variations occurred within the VI and VII leucine-rich repeats. The novel variant of Bernard-Soulier syndrome identified further suggests that the integrity of leucine-rich repeats is important for normal function of the GP Ib-IX-V receptor complex.

Novel Mutation in the Glycoprotein Ibβ in a Patient with Bernard-Soulier Syndrome: Possibility of Distant Parental Consanguinity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4689-4689
Author(s):  
Rami Mahfouz ◽  
Carsten Bergmann ◽  
Zaher Otrock ◽  
Hanno Bolz ◽  
Samar A. Muwakkit
Keyword(s):  
Conflicts Of Interest ◽  
Novel Mutation ◽  
High Dose ◽  
Giant Platelets ◽  
Parental Consanguinity ◽  
Cell Counts ◽  
Platelet Disorder ◽  
Recurrent Epistaxis ◽  
History Of ◽  
Bernard Soulier Syndrome

Abstract Abstract 4689 Introduction: Bernard-Soulier syndrome (BSS) is a rare autosomal recessive disorder characterized by a prolonged skin-bleeding time and thrombocytopenia with giant platelets. The hallmark of BSS is an abnormal platelet attachment to the vessel wall due to reduced or abnormal glycoprotein (GP) Ib/IX/V complex. We present a case of BSS in a 14-month-old boy caused by a novel genetic mutation. Patient and methods: A 14-month-old Syrian boy was referred to our medical center with a history of easy bruisability, epistaxis, and low platelet counts since the age of 5 months. He was the second child of non-consanguineous parents. His parents and siblings were negative for a history of bleeding disorders. His nephew was reported to have low platelets counts. The patient was hospitalized in Syria several times and was initially diagnosed as having idiopathic thrombocytopenic purpura. He received corticosteroids and high-dose intravenous immunoglobulin both of which were ineffective. He also received platelet transfusion for recurrent epistaxis, which improved as per the parents. The possibility of a platelet disorder was raised and he was referred to our center for further investigation. Physical examination showed bruises over the face and extremities. Abdominal examination was negative for hepatosplenomegaly. There were no congenital abnormalities. His platelet count was 100 × 109/l. The presence of giant platelets was noted on blood film inspection. Other blood cell counts, blood chemistry and coagulation studies, including von Willebrand factor (vWF) antigen and activity, were within the normal range. A clinical diagnosis of BSS was made. Peripheral blood was obtained for genetic testing. DNA sequencing and analysis The initial extraction of the DNA material was done using the PEL-FREEZ extraction kit (PEL-FREEZ, DYNAL, USA) and genomic material stored at −80°C. We performed direct sequencing of the entire coding regions including exon-intron boundaries of the GPIbα and GPIbβ genes (GenBank: NM_000173.5 and NM_000407.4; mutation numbering + 1 corresponds to the A of the ATG-translation initiation codon, respectively). Genomic DNA from patient was amplified by PCR with oligonucleotide primers complementary to flanking intronic sequences. Primers were designed using the Primer3 program (http://www-genome.wi.mit.edu/cgi-bin/primer/primer3.cgi) (primer sequences and PCR conditions are available on request). PCR products were sequenced employing ABI BigDye chemistry (Applied Biosystems, Darmstadt, Germany). The same primers as for PCR were used as sequencing primers. Samples were run and analyzed on an ABI PRISM 3130 genetic analyzer (Applied Biosystems). Conclusion: We present a case of BSS in a 14-month-old boy caused by a novel nonsense mutation (c.423C>A) in the GPIbβ gene. Knowing that we are dealing with a very rare syndrome, the detected mutation in our patient was homozygous. Although the parents were non-consanguineous, we believe that they were related in a distant parental consanguinity which the parents and their family were not aware of. Disclosures: No relevant conflicts of interest to declare.

scholarly journals LAD-1/variant syndrome is caused by mutations in FERMT3

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4740-4746 ◽  
Author(s):  
Taco W. Kuijpers ◽  
Edith van de Vijver ◽  
Marian A. J. Weterman ◽  
Martin de Boer ◽  
Anton T. J. Tool ◽  
...  
Keyword(s):  
Stop Codon ◽  
Leukocyte Adhesion ◽  
Genetic Defect ◽  
Premature Stop Codon ◽  
Focal Adhesions ◽  
Splice Site Mutation ◽  
Homozygosity Mapping ◽  
Convincing Evidence ◽  
Chromosome 11 ◽  
Site Mutation

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.

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