Proceedings: Differences in platelet storage pool deficiency (SPD) of Hermansky Pudlak syndrome (HPS) and non-albinos (NA).
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Adenine Nucleotides↗
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Results for “Platelet Storage Pool Deficiency”
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Ultrastructure of resting and activated storage pool deficient platelets from animals with the Chédiak-Higashi syndrome.
The ultrastructural of platelets from Chédiak-Higashi (CH) and normal cattle, mink, and cats at rest was studied. Platelets from CH animals had a virtual absence of platelet dense granules. Alpha granules, amorphous membrane-surrounded structures, mitochondria, and microtubules of CH bovine platelets were similar in number and appearance to those in normal bovine platelets. Giant CH granules, present in other cells and considered diagnostic of the syndrome, could not be identified in platelets from CH animals. The open canalicular system and dense tubule system were not readily identifiable in resting bovine platelets. The ultrastructure of normal and CH cattle platelets was evaluated at various stages of ADP-induced aggregation. After platelets changed shape during the first phase of aggregation, the ultrastructural appearance of CH platelets was similar to that of normal platelets. The CH platelets composing the aggregates during irreversible aggregation did not appear as activated as did normal platelets, even though the aggregation tracings were similar. Normal and CH cattle platelets treated with thrombin appeared morphologically similar and were characterized by centrifugal movement of granules.
Adenosine Diphosphate↗
Specific correction of impaired acid hydrolase secretion in storage pool-deficient platelets by adenosine diphosphate.
Storage pool-deficient (SPD) platelets, which have decreased amounts of dense-granule and/or alpha-granule constituents, contain normal amounts of lysosomal acid hydrolases, but in some cases exhibit impaired secretion of these enzymes. We examined this impaired secretion response in SPD patients with varying extents of granule deficiencies, and determined the effects of added dense-granule constituents. Acid hydrolase secretion was impaired in patients with severe dense-granule deficiencies, but not in patients with lesser dense-granule deficiencies, including those with alpha-granule deficiencies as well. When dense-granule constituents (ADP, ATP, serotonin, Ca+2, pyrophosphate) were added to gel-filtered platelets, ADP, but none of the other constituents, completely corrected the impairment of thrombin and A23187-induced secretion in SPD platelets. The concentration of ADP required to normalize thrombin-induced secretion varied markedly, from 0.01 to 10 microM, among the individual patients. Fixation of platelets with formaldehyde before centrifugation did not prevent the enhancement of secretion by ADP. Excess ATP, which acts as a specific antagonist of ADP-mediated responses, completely blocked this enhancement of secretion in SPD platelets by ADP, and partially inhibited acid hydrolase secretion induced by low, but not high, concentrations of thrombin in normal platelets as well. Treatment of normal platelets with acetylsalicylic acid in vivo, but not in vitro, produced an impairment of acid hydrolase secretion similar in extent to that in SPD platelets, but which could not be completely corrected by added ADP. One possible explanation of these results is that the impairment of acid hydrolase secretion may be secondary to the dense-granule deficiency in SPD platelets, and that secreted ADP may potentiate the lysosomal secretion response in normal platelets as well.
Adenosine Diphosphate↗
Identification of a novel transcript produced by the gene responsible for the Hermansky-Pudlak syndrome in Puerto Rico.
Hermansky-Pudlak Syndrome (HPS) is a rare, autosomal recessive disorder that is characterized by oculocutaneous albinism, a predisposition to mild bleeding caused by storage-pool deficient platelets, and a ceroid storage disorder. A gene responsible for HPS in Puerto Rico maps to chromosome 10q2 and isolation of the gene has been reported. We have now identified a variant HPS cDNA that contains the same 5' sequence as the published HPS gene and a unique 3' sequence. Analysis of genomic DNA suggests that the two cDNA are derived from alternative transcripts of a single gene; two polyadenylated transcripts were found in normal human melanocytes, human bone marrow cells, human melanoma cells, lymphoblastoid cell lines, and megakaryocytic leukemia cells by reverse transcriptase polymerase chain reaction and northern analysis. The splicing exhibited by this gene is identical to the splicing found to produce two alternative transcripts of the Chediak-Higashi Syndrome gene, another pigment disorder exhibiting platelet storage pool deficiency. These studies show that the HPS gene on chromosome 10 is complex and may have more than one biologically active transcript.
Albinism, Oculocutaneous↗
Collagen-induced rat platelet reactivity is enhanced in whole blood in both the presence and absence of dense granule secretion.
Collagen induced aggregation, ATP secretion and thromboxane (TxB2) generation of storage pool deficient platelets were compared to normal platelets of closely related rat strains. Platelet function was monitored in citrated-platelet-rich-plasma (PRP) and citrated whole blood. Wistar (W) and fawn-hooded (FH) rat strains and their F2 hybrids were utilized. The W strain, which is ancestral to the FH strain, is not storage pool deficient while the FH strain is. This was manifested by the total lack of collagen induced ATP secretion from platelets of the FH strain while the platelets of the W strain secreted normally. Utilizing platelets from the F2 generation of WxFH matings, the absence of dense granule secretion (ATP) from the FH platelets, as well as other platelet defects of FH rats, were shown to be associated with homozygosity for the red-eyed dilution gene [r]. The non-secreting FH platelets were utilized to determine the effects of secreted dense granule constituents upon collagen induced aggregation and TxB2 generation. The non-secreting storage pool deficient platelets did aggregate and did generate TxB2 upon stimulation with collagen; however, the storage pool deficient FH platelets demonstrated less TxB2 generation and did not aggregate as effectively as the normally secreting platelets of the W strain. When evaluating collagen induced platelet function in whole blood as compared to PRP, the storage pool deficient platelets remained less reactive than normally secreting platelets, but both platelet types demonstrated enhanced aggregation and increased TxB2 generation in whole blood.
Adenosine Triphosphate↗
Hermansky-Pudlak syndrome (HPS). An epidemiologic study.
A study of albinism in Puerto Rico identified 693 persons with albinism. Among these, the type of albinism was determined in 595, Hermansky-Pudlak syndrome (HPS) was found in 495. Approximately five of every six Puerto Rican albinos had HPS. The highest prevalence of HPS yet reported was in the northwestern quarter of the island where at least 1 in 1,800 persons had HPS, and approximately 1 in 21 were carriers. The HPS albino pigment phenotype was variable, and HPS albinos phenotypically resembled other types of oculocutaneous and ocular albinos. Ceroid storage was also variable. The consistent finding in HPS was storage pool deficient platelets. HPS is best diagnosed by lack of platelet dense bodies seen by electron microscopy. Evidence from family studies indicates that HPS is a distinct disorder due to the pleiotropic effects of a single gene mutation or a small deletion.
Albinism↗
Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency.
Hermansky-Pudlak syndrome (HPS), consisting of oculocutaneous albinism and a bleeding diathesis due to the absence of platelet dense granules, displays extensive locus heterogeneity. HPS1 mutations cause HPS-1 disease, and ADTB3A mutations cause HPS-2 disease, which is known to involve abnormal intracellular vesicle formation. A third HPS-causing gene, HPS3, was recently identified on the basis of homozygosity mapping of a genetic isolate of HPS in central Puerto Rico. We now describe the clinical and molecular characteristics of eight patients with HPS-3 who are of non-Puerto Rican heritage. Five are Ashkenazi Jews; three of these are homozygous for a 1303+1G-->A splice-site mutation that causes skipping of exon 5, deleting an RsaI restriction site and decreasing the amounts of mRNA found on northern blotting. The other two are heterozygous for the 1303+1G-->A mutation and for either an 1831+2T-->G or a 2621-2A-->G splicing mutation. Of 235 anonymous Ashkenazi Jewish DNA samples, one was heterozygous for the 1303+1G-->A mutation. One seven-year-old boy of German/Swiss extraction was compound heterozygous for a 2729+1G-->C mutation, causing skipping of exon 14, and resulting in a C1329T missense (R396W), with decreased mRNA production. A 15-year-old Irish/English boy was heterozygous for an 89-bp insertion between exons 16 and 17 resulting from abnormal splicing; his fibroblast HPS3 mRNA is normal in amount but is increased in size. A 12-year-old girl of Puerto Rican and Italian background has the 3,904-bp founder deletion from central Puerto Rico on one allele. All eight patients have mild symptoms of HPS; two Jewish patients had received the diagnosis of ocular, rather than oculocutaneous, albinism. These findings expand the molecular diagnosis of HPS, provide a screening method for a mutation common among Jews, and suggest that other patients with mild hypopigmentation and decreased vision should be examined for HPS.
Adaptor Protein Complex 3↗
Platelet aggregation, storage pool deficiency, and protein phosphorylation in mice with Chediak-Higashi syndrome.
The beige (bgJ/bgJ) mouse is a well-described murine model of Chediak-Higashi syndrome. Platelet function was examined in normal and beige mice to better characterize the defective aggregation response in platelets from mice with Chediak-Higashi syndrome. Platelet aggregation after collagen, thrombin, and phorbol-12-myristate 13-acetate stimulation was significantly (P less than 0.025) decreased in platelets from beige mice, relative to platelets from normal mice. Compared with beige and normal mice, those heterozygous for the bg trait had intermediate responses to collagen and thrombin, but not phorbol-12-myristate 13-acetate. The defect(s) in aggregation of platelets from beige mice was associated with a dense granule storage pool deficiency and decreased stores of serotonin and adenine nucleotides in platelets. Mice heterozygous for the bg trait had normal platelet serotonin and adenine nucleotide concentrations. Platelets from beige mice were approximately 10 times more sensitive to prostacyclin inhibition of collagen-induced aggregation than were platelets from control mice. However, a significant difference in platelet cyclic AMP concentration was not apparent between beige and normal mice after prostacyclin stimulation. Platelet endoperoxide synthesis measured by quantification of thromboxane B2, was normal in beige mice. Protein phosphorylation patterns in mouse platelets were similar to those seen in human platelets. Thrombin and collagen-induced [32P] phosphorylation of 40- and 20-kD proteins in platelets from normal and beige mice was similar. Results indicate that the biochemical defect(s) in platelet function in beige mice is partially attributable to storage pool deficiency and does not result in an absolute defect in phosphorylation of 40- and 20-kD proteins.
Animals↗
Morphologic and hematologic characteristics of storage pool deficiency in beige rats (Chédiak-Higashi syndrome of rats).
Characterization of beige rats as having a platelet storage pool deficiency (SPD) was undertaken. Platelets from beige rats, an animal model of Chédiak-Higashi syndrome (CHS), completely lacked the ability to aggregate when stimulated with high dosages of collagen (50 micrograms/ml), and lacked secondary aggregation induced by adenosine diphosphate (ADP). Concentrations of ADP, ATP, and serotonin in the platelets of beige rats were significantly lower than those of control rats. However, platelet count remained within normal values. Electron microscopy revealed that platelets had fewer dense granules, whereas other organelles had normal structure. This morphologic and functional evidence confirms that platelets of beige rats have the typical characteristics of SPD.
Adenosine Diphosphate↗
The storage pool deficiency in platelets from humans with the Chédiak-Higashi syndrome: study of six patients.
Functional and biochemical studies of platelets from human Chédiak-Higashi syndrome (CHS) are scarce and/or incomplete. In the present report, the aggregation response to a variety of inducers of platelet aggregation, the content of the dense granule constituents ATP, ADP, serotonin and calcium, the secretion of ATP, ADP, and calcium induced by thrombin, the total content of magnesium, the incorporation of 14C-adenine in the cytoplasmic pool of adenine nucleotides, as well as the content of intracellular cyclic-AMP, have been quantitated in six patients with CHS. Furthermore, data is presented on the kinetics of uptake of radiolabelled serotonin and its storage in human CHS platelets. An abnormal aggregation behaviour was found in all patients. However, the response of CHS platelets to the different inducers studied did not show a uniform pattern. The total content and the maximal amounts of the dense granule constituents secretable by thrombin were greatly decreased in all six patients. Total magnesium content was similar to that of normal platelets. The ATP/ADP ratio was higher than in controls. Uptake of radiolabelled serotonin by CHS platelets closely followed the uptake by normal platelets; during the first 2-3 min, however, incorporation of the amine by CHS platelets came rapidly to a plateau which contrasts with the steady, linear increase in uptake found in controls. CHS platelets loaded with radiolabelled serotonin and gel-filtered, showed a spontaneous release of radioactivity not observed in normal platelets under the same conditions. The cyclic-AMP content of CHS platelets was similar to that of normals. In contrast to platelets from patients with storage pool disease, the secretable calcium from CHS platelets represents a 67% of total platelet calcium (61% in normals), suggesting that the absolute values for the non-secretable portion in CHS platelets must be very low. The results reported confirm the existence of a true storage pool deficiency of the dense granule constituents as a common defect in CHS platelets. The variety of responses among patients, to the different aggregatory stimuli studied, can not be solely ascribed to the storage pool deficiency described.
Adenine Nucleotides↗
The murine pallid mutation is a platelet storage pool disease associated with the protein 4.2 (pallidin) gene.
Pallid is one of 12 independent murine mutations with a prolonged bleeding time that are models for human platelet storage pool deficiencies in which several intracellular organelles are abnormal. We have mapped the murine gene for protein 4.2 (Epb4.2) to chromosome 2 where it co-localizes with pallid. Southern blot analyses suggest that pallid is a mutation in the Epb4.2 gene. Northern blot analyses demonstrate a smaller than normal Epb4.2 transcript in affected pallid tissues, such as kidney and skin. This is the first gene defect to be associated with a platelet storage pool deficiency, and may allow the identification of a novel structure or biological pathway that influences granulogenesis.
Animals↗
Compartmentation of 4,6-difluoro-5HT studied by nuclear magnetic resonance in normal and CHS bovine platelets.
A platelet storage pool deficiency (SPD) is present in platelets from cattle with the Chediak-Higashi syndrome (CHS). The most plausible hypothesis for the SPD is that dense granule precursors are simply not formed in CHS megakaryocytes. There is, however, evidence that some recently acquired 5-hydroxytryptamine (5HT) is located in granules and that the granules have an acidic interior. To obtain a greater understanding of the processing of 5HT by SPD platelets, normal and CHS platelets were incubated with 4,6-difluoro-5HT and studied by 19F NMR at 188 mHz. Normal platelets contained 2 compartments for 4,6-difluoro-5HT as indicated by 2 well-developed resonances for each 19F. The resonances were unequal in magnitude. The predominant resonance broadened with lower temperatures and was absent in CHS bovine platelets; it was, therefore, the dense granule compartment. There was only 1 resonance for each 19F in CHS platelets. The chemical shift was identical to the minor resonance, or non-dense granule resonance, found in normal bovine platelets but the resonance width was increased, indicating that some non-dense granule 4,6-difluoro-5HT was in a more restricted environment within CHS platelets than it was in normal platelets.
Animals↗
Decreased content and surface expression of alpha-granule membrane protein GMP-140 in one of two types of platelet alpha delta storage pool deficiency.
To determine whether alpha-granule membranes are present in platelets of patients with storage pool deficiencies of both alpha and dense granules (alpha delta-SPD), we examined the content and surface expression of the alpha-granule membrane protein GMP-140 in one patient (J.C.) with a severe alpha-granule deficiency and in three members of a family (family C) with milder alpha-granule deficiencies. Surface expression of GMP-140 in stimulated platelets, assessed by flow cytometric measurements of the binding of two anti-GMP-140 monoclonal antibodies, was 24-38% of normal values in platelets from patient J.C., vs. 60-95% of normal values in family C. Total platelet content of GMP-140, determined in platelet lysates by antigen-capture ELISA, was 49% of normal in patient J.C., but normal in the members of family C. Platelets of patient J.C. were found to be heterogeneous with respect to GMP-140 content and surface expression by both flow cytometry and immunogold electron microscopy. Approximately 80% of her platelets expressed little or no GMP-140 after stimulation, whereas the remaining 20% expressed normal amounts of GMP-140 and showed extensive immunogold labeling of typical alpha-granules and clear vacuoles. No such heterogeneity was found in platelets from family C. These findings in the severe alpha delta-SPD patient are in clear contrast to the observations of normal GMP-140 content in the three other alpha delta-SPD patients, and in patients with the gray platelet syndrome, reported previously by others. These results illustrate the phenotypic heterogeneity of alpha-granule deficiencies in human platelets, and suggest that a defect in granule formation in the megakaryocytes may account for the alpha-granule defect in at least one form of alpha delta-SPD.
Adult↗
Regional analysis of 5-HT1A and 5-HT2 receptors in the fawn-hooded rat.
The Fawn-Hooded strain of rats exhibits a hemorrhagic disorder, known as platelet storage pool deficiency. In addition to the platelet dysfunction, there is an altered response to certain serotonin drugs. To assess the characteristics of the binding to 5-HT1A and 5-HT2 receptors in this strain, regions of the brain from Fawn-Hooded, Sprague-Dawley and Wistar male rats were examined. The drug [3H]8-OH-DPAT was used to label 5-HT1A receptors and the Kd values for frontal cortex, hippocampus, striatum, hypothalamus and brainstem were similar in all three strains of rat. As with the 5-HT1A receptors, no differences were observed in the Kd values for 5-HT2 receptors, in any of the regions examined, among the three strains. However, the Bmax for the binding of [3H]8-OH-DPAT in the striatum and brainstem of Fawn-Hooded rats was less than in the Sprague-Dawley and Wistar animals. Furthermore, 5-HT2 receptors displayed a greater Bmax value in the striatum and in the frontal cortex of Fawn-Hooded animals, compared to Sprague-Dawley and Wistar rats. These differences in receptors are consistent with previous studies in which Fawn-Hooded rats were found to have altered serotonergic function, relative to Wistar and Sprague-Dawley animals.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Electron dense chains and clusters in human platelets.
Human platelets contain dense organelles that serve as storage sites for adenine nucleotides and serotonin. They also contain calcium and phosphate responsible for the opacity of dense bodies in the electron microscope. The present study has shown that there are also bead-like structures and clusters of beads that are electron opaque when viewed by the whole mount technique. Their origin and function are not known. However, their presence might interfere with the accuracy of imaging techniques currently being used to measure the number and volume of dense bodies in patients with platelet storage pool deficiency.
Adult↗
The rat Ruby ( R) locus is Rab38: identical mutations in Fawn-hooded and Tester-Moriyama rats derived from an ancestral Long Evans rat sub-strain.
Hermansky-Pudlak syndrome (HPS) is a group of rare, recessive disorders in which oculocutaneous albinism, progressive pulmonary fibrosis, bleeding diathesis, and other abnormalities result from defective biogenesis of multiple cytoplasmic organelles. Seven different HPS genes are known in humans; in mouse, at least 16 loci are associated with HPS-like mutant phenotypes. In the rat, only two HPS models are known, Fawn-hooded (FH) and Tester Moriyama (TM), non-complementing strains in which HPS-like hypopigmentation and platelet storage pool deficiency result from a mutation of the Ruby (red eyed dilution; R) locus on Chromosome (Chr) 1. We have identified the R locus as the Rab38 gene, establishing that rat R is homologous to mouse chocolate ( cht). Further, we show that FH and TM rats have identical Rab38 Met1Ile mutations, occurring on an identical Chr 1 marker allele haplotype, indicating that these two strains derive from a common ancestor. This ancestor appears to have been a sub-strain of the outbred Long Evans (LE) strain, and several modern LE sub-strains carry the Rab38 Met1Ile R mutation on the same Chr 1 marker haplotype. These findings have significant implications for the many past and ongoing studies that involve the FH and LE-derivative rat strains. Hermansky-Pudlak syndrome (HPS; MIM 203300) is a group of autosomal recessive diseases in which oculocutaneous albinism (OCA), progressive and fatal pulmonary fibrosis, and bleeding diathesis due to platelet storage pool deficiency result from defects in the biogenesis of specific cytoplasmic organelles and granules: melanosomes, lysosomes, and platelet dense granules. In humans, seven different HPS genes are known. In the mouse, at least 16 loci associated with HPS-like mutant phenotypes are known, seven of which are homologous to the human HPS loci.
Animals↗
Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2.
Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disease consisting of oculocutaneous albinism and a storage pool deficiency resulting from absent platelet dense bodies. The disorder is genetically heterogeneous. The majority of patients, including members of a large genetic isolate in northwest Puerto Rico, have mutations in HPS1. Another gene, ADTB3A, was shown to cause HPS-2 in two brothers having compound heterozygous mutations that allowed for residual production of the gene product, the beta3A subunit of adaptor complex-3 (AP-3). This heterotetrameric complex serves as a coat protein-mediating formation of intracellular vesicles, e.g. the melanosome and platelet dense body, from membranes of the trans-Golgi network. We determined the genomic organization of the human ADTB3A gene, with intron/exon boundaries, and describe a third patient with beta3A deficiency. This 5-y-old boy has two nonsense mutations, C1578T (R-->X) and G2028T (E-->X), which produce no ADTB3A mRNA and no beta3A protein. The associated mu3 subunit of AP-3 is also entirely absent. In fibroblasts, the cell biologic concomitant of this deficiency is robust and aberrant trafficking through the plasma membrane of LAMP-3, an integral lysosomal membrane protein normally carried directly to the lysosome. The clinical concomitant is a severe, G-CSF-responsive neutropenia in addition to oculocutaneous albinism and platelet storage pool deficiency. Our findings expand the molecular, cellular, and clinical spectrum of HPS-2 and call for an increased index of suspicion for this diagnosis among patients with features of albinism, bleeding, and neutropenia.
Adaptor Protein Complex 3↗
Conditioned place preference/aversion to fenfluramine in fawn hooded and sprague-Dawley rats.
The Fawn Hooded (FH) rat strain possesses a genetic platelet storage pool deficiency which leads to an impaired capacity for platelets to store and release serotonin. While the relationship between this deficit and possible alterations in brain serotonergic levels or function remains unclear, numerous behavioral studies have indicated that FH rats exhibit differential responses to serotonergic agonists and antagonist relative to other strains. The current study used the conditioned place preference paradigm to examine the ability of fenfluramine to produce a conditioned place preference (CPP) or aversion (CPA) in FH and Sprague-Dawley (SD) rats. Results indicated that fenfluramine failed to produce CPP or CPA in SD rats, but did produce a CPA in FH rats. Results are discussed in terms of the use of conditioned place preference to assess putative differences in serotonergic functioning in FH rats.
Animals↗