scholarly journals Platelet storage pool deficiency in mouse pigment mutations associated with seven distinct genetic loci

Blood ◽  
1984 ◽  
Vol 63 (3) ◽  
pp. 536-544 ◽  
Author(s):  
EK Novak ◽  
SW Hui ◽  
RT Swank
Keyword(s):  
Lysosomal Enzyme ◽  
Human Platelet ◽  
Adenosine Diphosphate ◽  
Dense Granule ◽  
Enzyme Secretion ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage ◽  
Storage Pool Disease ◽  
Experimental Injury

Abstract Seven mouse pigment mutants, which have alterations at distinct genes, are known to have a defect in kidney lysosomal enzyme secretion. Two of these, beige and pale ear, have a bleeding abnormality associated with a deficiency in the number of platelet dense granules. In the present study, five other mutants with defective lysosomal enzyme secretion-- pearl, pallid, light ear, maroon, and ruby-eye--were likewise found to have abnormally prolonged bleeding times after experimental injury. Platelet counts were similar to those of normal mice, but the platelet dense granule components serotonin, adenosine triphosphate (ATP), and adenosine diphosphate (ADP) and morphologically identifiable dense granules were markedly reduced in these mutants. The capacity to accumulate exogenous 3H-serotonin in platelets was reduced 2–3-fold. Thrombin-stimulated secretion of 3H-serotonin was slightly decreased in all mutants. However, the seven mutants could be subdivided into three groups based on the degree of secretion of lysosomal enzymes after thrombin stimulation. Thus, all seven mouse pigment mutants have symptoms consistent with platelet storage pool deficiency and may serve as useful animal models for specific types of human platelet storage pool disease. Also, the results emphasize the genetic, morphological, and functional interrelatedness of three organelles: melanosomes, lysosomes, and platelet dense granules.

scholarly journals Platelet storage pool deficiency in mouse pigment mutations associated with seven distinct genetic loci

Blood ◽  
1984 ◽  
Vol 63 (3) ◽  
pp. 536-544 ◽  
Author(s):  
EK Novak ◽  
SW Hui ◽  
RT Swank
Keyword(s):  
Lysosomal Enzyme ◽  
Human Platelet ◽  
Adenosine Diphosphate ◽  
Dense Granule ◽  
Enzyme Secretion ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage ◽  
Storage Pool Disease ◽  
Experimental Injury

Seven mouse pigment mutants, which have alterations at distinct genes, are known to have a defect in kidney lysosomal enzyme secretion. Two of these, beige and pale ear, have a bleeding abnormality associated with a deficiency in the number of platelet dense granules. In the present study, five other mutants with defective lysosomal enzyme secretion-- pearl, pallid, light ear, maroon, and ruby-eye--were likewise found to have abnormally prolonged bleeding times after experimental injury. Platelet counts were similar to those of normal mice, but the platelet dense granule components serotonin, adenosine triphosphate (ATP), and adenosine diphosphate (ADP) and morphologically identifiable dense granules were markedly reduced in these mutants. The capacity to accumulate exogenous 3H-serotonin in platelets was reduced 2–3-fold. Thrombin-stimulated secretion of 3H-serotonin was slightly decreased in all mutants. However, the seven mutants could be subdivided into three groups based on the degree of secretion of lysosomal enzymes after thrombin stimulation. Thus, all seven mouse pigment mutants have symptoms consistent with platelet storage pool deficiency and may serve as useful animal models for specific types of human platelet storage pool disease. Also, the results emphasize the genetic, morphological, and functional interrelatedness of three organelles: melanosomes, lysosomes, and platelet dense granules.

scholarly journals The mouse pale ear pigment mutant as a possible animal model for human platelet storage pool deficiency

Blood ◽  
1981 ◽  
Vol 57 (1) ◽  
pp. 38-43 ◽  
Author(s):  
EK Novak ◽  
SW Hui ◽  
RT Swank
Keyword(s):  
Animal Model ◽  
Human Platelet ◽  
Dense Granule ◽  
Subcellular Organelles ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Protein ◽  
Platelet Storage ◽  
Storage Pool Disease ◽  
Experimental Injury

Abstract The mouse pigment mutant pale ear, ep/ep, which has a defect in kidney lysosomal enzyme secretion, had prolonged bleeding on experimental injury. Platelet counts and platelet protein did not differ from normal. There was, however, a deficiency in the platelet dense granule contents, serotonin, ATP, and ADP. Furthermore, a marked reduction of platelet dense granules was observed by electron microscopy. The results suggest that pale ear is a useful animal model in the study of platelet storage pool disease. Studies on this mutant and other pigment mutants have established that one gene can regulate at least three subcellular organelles, including the melanosome, the lysosome, and the platelet dense granule.

scholarly journals The mouse pale ear pigment mutant as a possible animal model for human platelet storage pool deficiency

Blood ◽  
1981 ◽  
Vol 57 (1) ◽  
pp. 38-43 ◽  
Author(s):  
EK Novak ◽  
SW Hui ◽  
RT Swank
Keyword(s):  
Animal Model ◽  
Human Platelet ◽  
Dense Granule ◽  
Subcellular Organelles ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Protein ◽  
Platelet Storage ◽  
Storage Pool Disease ◽  
Experimental Injury

The mouse pigment mutant pale ear, ep/ep, which has a defect in kidney lysosomal enzyme secretion, had prolonged bleeding on experimental injury. Platelet counts and platelet protein did not differ from normal. There was, however, a deficiency in the platelet dense granule contents, serotonin, ATP, and ADP. Furthermore, a marked reduction of platelet dense granules was observed by electron microscopy. The results suggest that pale ear is a useful animal model in the study of platelet storage pool disease. Studies on this mutant and other pigment mutants have established that one gene can regulate at least three subcellular organelles, including the melanosome, the lysosome, and the platelet dense granule.

scholarly journals Immature dense granules in platelets from mice with platelet storage pool disease

Blood ◽  
1987 ◽  
Vol 69 (5) ◽  
pp. 1300-1306 ◽  
Author(s):  
M Reddington ◽  
EK Novak ◽  
E Hurley ◽  
C Medda ◽  
MP McGarry ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Dense Granule ◽  
Mutant Mice ◽  
Normal Numbers ◽  
Group Of Seven ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage ◽  
Transmission Electron ◽  
Storage Pool Disease

Mepacrine uptake into platelets and bone marrow megakaryocytes was analyzed to further characterize the dense granule defects in a group of seven mouse pigment mutants that have characteristics of platelet storage pool disease (SPD). In contrast to our previous studies using electron microscopy, this method revealed that all mutants had normal numbers of dense granules. However, total mepacrine uptake in all mutant platelets was significantly diminished to less than 50% of normal uptake. Also, the flashing phenomenon observed when normal dense granules are irradiated with ultraviolet light was either greatly diminished or absent when platelets of individual mutants were similarly irradiated. Therefore the principal defect in the mutant platelets is an inability to accumulate dense granule contents rather than an absence of the granules. Mepacrine uptake into megakaryocytes was indistinguishable in normal and mutant mice. This indicates the mutant dense granule defects appear either very late in megakaryocyte development or early in platelet formation in correlation with development of the mature dense granule. By standard transmission electron microscopy we have not been able to detect gross structural or subcellular abnormalities in either platelets or megakaryocytes of mutant mice. It appears all seven mutants produce immature or functionally abnormal dense granules.

scholarly journals Immature dense granules in platelets from mice with platelet storage pool disease

Blood ◽  
1987 ◽  
Vol 69 (5) ◽  
pp. 1300-1306 ◽  
Author(s):  
M Reddington ◽  
EK Novak ◽  
E Hurley ◽  
C Medda ◽  
MP McGarry ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Dense Granule ◽  
Mutant Mice ◽  
Normal Numbers ◽  
Group Of Seven ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage ◽  
Transmission Electron ◽  
Storage Pool Disease

Abstract Mepacrine uptake into platelets and bone marrow megakaryocytes was analyzed to further characterize the dense granule defects in a group of seven mouse pigment mutants that have characteristics of platelet storage pool disease (SPD). In contrast to our previous studies using electron microscopy, this method revealed that all mutants had normal numbers of dense granules. However, total mepacrine uptake in all mutant platelets was significantly diminished to less than 50% of normal uptake. Also, the flashing phenomenon observed when normal dense granules are irradiated with ultraviolet light was either greatly diminished or absent when platelets of individual mutants were similarly irradiated. Therefore the principal defect in the mutant platelets is an inability to accumulate dense granule contents rather than an absence of the granules. Mepacrine uptake into megakaryocytes was indistinguishable in normal and mutant mice. This indicates the mutant dense granule defects appear either very late in megakaryocyte development or early in platelet formation in correlation with development of the mature dense granule. By standard transmission electron microscopy we have not been able to detect gross structural or subcellular abnormalities in either platelets or megakaryocytes of mutant mice. It appears all seven mutants produce immature or functionally abnormal dense granules.

scholarly journals Platelet storage pool deficiency associated with inherited abnormalities of the inner ear in the mouse pigment mutants muted and mocha

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 2036-2044 ◽  
Author(s):  
RT Swank ◽  
M Reddington ◽  
O Howlett ◽  
EK Novak
Keyword(s):  
Inner Ear ◽  
Lysosomal Enzyme ◽  
Enzyme Secretion ◽  
Proximal Tubule Cells ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage ◽  
Whole Mount ◽  
Hermansky Pudlak Syndrome ◽  
Tubule Cells

Abstract Several inherited human syndromes have combined platelet, auditory, and/or pigment abnormalities. In the mouse the pallid pigment mutant has abnormalities of the otoliths of the inner ear together with a bleeding abnormality caused by platelet storage pool deficiency (SPD). To determine if this association is common, two other mouse pigment mutants, muted and mocha, which are known to have inner ear abnormalities, were examined for hematologic abnormalities. Both mutants had prolonged bleeding times accompanied by abnormalities of dense granules as determined by whole mount electron microscopy of platelets and by labeling platelets with mepacrine. When mutant platelets were treated with collagen, there was minimal secretion of adenosine triphosphate and aggregation was reduced. Lysosomal enzyme secretion in response to thrombin treatment was partially reduced in muted platelets and markedly reduced in mocha platelets. Similar reductions in constitutive lysosomal enzyme secretion from kidney proximal tubule cells were noted in the two mutants. These studies show that several mutations that cause pigment dilution and platelet SPD are associated with abnormalities of the inner ear. Also, these mutants, like previously described mouse pigment mutants, are models for human Hermansky-Pudlak syndrome and provide additional examples of single genes that simultaneously affect melanosomes, lysosomes, and platelet dense granules.

scholarly journals Platelet storage pool deficiency associated with inherited abnormalities of the inner ear in the mouse pigment mutants muted and mocha

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 2036-2044 ◽  
Author(s):  
RT Swank ◽  
M Reddington ◽  
O Howlett ◽  
EK Novak
Keyword(s):  
Inner Ear ◽  
Lysosomal Enzyme ◽  
Enzyme Secretion ◽  
Proximal Tubule Cells ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage ◽  
Whole Mount ◽  
Hermansky Pudlak Syndrome ◽  
Tubule Cells

Several inherited human syndromes have combined platelet, auditory, and/or pigment abnormalities. In the mouse the pallid pigment mutant has abnormalities of the otoliths of the inner ear together with a bleeding abnormality caused by platelet storage pool deficiency (SPD). To determine if this association is common, two other mouse pigment mutants, muted and mocha, which are known to have inner ear abnormalities, were examined for hematologic abnormalities. Both mutants had prolonged bleeding times accompanied by abnormalities of dense granules as determined by whole mount electron microscopy of platelets and by labeling platelets with mepacrine. When mutant platelets were treated with collagen, there was minimal secretion of adenosine triphosphate and aggregation was reduced. Lysosomal enzyme secretion in response to thrombin treatment was partially reduced in muted platelets and markedly reduced in mocha platelets. Similar reductions in constitutive lysosomal enzyme secretion from kidney proximal tubule cells were noted in the two mutants. These studies show that several mutations that cause pigment dilution and platelet SPD are associated with abnormalities of the inner ear. Also, these mutants, like previously described mouse pigment mutants, are models for human Hermansky-Pudlak syndrome and provide additional examples of single genes that simultaneously affect melanosomes, lysosomes, and platelet dense granules.

scholarly journals Storage Pool Disease: Evidence for Clinical and Biochemical Heterogeneity

1977 ◽  
Author(s):  
H. J. Weiss ◽  
B. A. Lages ◽  
L. D. Witte ◽  
K. L. Kaplan ◽  
DeW S. Goodman ◽  
...  
Keyword(s):  
Dense Granule ◽  
Second Phase ◽  
Platelet Factor ◽  
Cultured Fibroblasts ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage ◽  
Absolute Requirement ◽  
Adp Release ◽  
Storage Pool Disease

Patients with platelet storage pool disease have decreased numbers and contents (ATP, ADP, serotonin, calcium) of the dense granules. Our studies on 14 patients with this disorder suggest considerable clinical and biochemical heterogeneity. The most pronounced dense granule defect (lowest levels of ATP and ADP, undetectable serotonin) was found in the 5 albinos with the Hermansky-Pudlak syndrome. One non-albino patient is unique in showing a decreased content of β thromboglobulin (βTG), platelet factor 4 (PF4), and the platelet growth factor (PtGF) that stimulated the proliferation of cultured fibroblasts and arterial smooth muscle cells. Her platelets also contained a decreased number of α granules in addition to decreased dense granules, suggesting that βTG, PF4, and PtGF are localized in specific α granules which are morphogenetically related to dense granules. Another patient was unique in that ADP, epinephrine, and arachidonic acid evoked completely normal aggregation responses, associated with normal production of platelet malondialdehyde. Since his platelets were markedly deficient in ADP, these findings provide further evidence that ADP release is not an absolute requirement for ‘second phase’ aggregation and that PGG2 or thromboxane A2 may directly aggregate platelets independent of ADP release. Variable defects in malondialdehyde production in other patients suggest further heterogeneity of the release defect in storage pool disease.

A Functional Basis For The Platelet Storage Pool Deficiency In Chediak-Higashi Cattle

1981 ◽  
Author(s):  
K M Meyers ◽  
M Fukami ◽  
H Holmsen
Keyword(s):  
Freeze Fracture ◽  
Subcellular Fractionation ◽  
Dense Granule ◽  
Bivalent Cation ◽  
Fibrous Matrix ◽  
Dense Granules ◽  
Storage Pool ◽  
Common Basis ◽  
Platelet Storage ◽  
Amine Storage

Platelets from cattle with the morphologic homolog of the Chediak-Higashi (CH) syndrome are essentially devoid of secretable nucleotides and serotonin. There are reduced but still substantial amounts of secretable calcium and magnesium. The storage pool deficiency may be, in part, due to a functional granule defect. Platelets from CH cattle take up serotonin and protect it from degradation for several hours. If these platelets are treated with thrombin, serotonin and bivalent cations are released by mechanisms similar to that of secretion, suggesting a granule location for the released serotonin and cations. This suggestion is verified by subcellular fractionation studies where platelets are first incubated with 14C-serotonin then lysed using a French press. Organelles were then separated on a sucrose gradient by centrifugation. Serotonin in normal bovine platelets is associated with the dense granule or pellet while in CH platelets serotonin is primarily found in a region of the sucrose density zone that in normal platelets contain alpha granules. These findings suggested that some granules in CH platelets are able to acquire the bivalent cation and amine but not the nucleotide component of the bivalent cation-nucleotide-amine storage complex that is thought to occur in normal dense granules.Ultrastructural identification of the serotonin-containing CH granule is not known. There are 2 identifiable granule populations in CH platelets, alpha granules and fibrous matrix granules. Based on serial sectioning freeze fracture and morphometric studies, there are less than 4 of these granules/platelet. Mepacrine studies also demonstrate 2 granule populations. One population has an incidence of 2 per granule and characteristics of normal dense granules. Since the number of fibrous matrix granules and mepacrine granules is similar, a common basis for these granules which has at least some dense granule characteristics, i.e., mepacrine storage, is suggested.

scholarly journals The response of platelets to epinephrine in storage pool deficiency-- evidence pertaining to the role of adenosine diphosphate in mediating primary and secondary aggregation

Blood ◽  
1988 ◽  
Vol 72 (5) ◽  
pp. 1717-1725 ◽  
Author(s):  
HJ Weiss ◽  
B Lages
Keyword(s):  
Platelet Aggregation ◽  
Receptor Agonist ◽  
Adenosine Diphosphate ◽  
Normal Subjects ◽  
Dense Granule ◽  
Binding Studies ◽  
Dense Granules ◽  
Storage Pool ◽  
Receptor Sites

Abstract Aggregation responses and thromboxane (Tx) formation in ten patients with storage pool deficiency (SPD) specific to the dense granules (delta-SPD) were studied to assess further the role of dense granule adenosine diphosphate (ADP) in mediating platelet aggregation by epinephrine. The ability of epinephrine to elicit secondary aggregation (SA) responses was highly variable in delta-SPD when tested at 5 mumol/L epinephrine, but was consistently abnormal when tested over a range of concentrations. The occurrence of SA in both delta-SPD patients and normal subjects was correlated with the magnitude of the rate of primary aggregation (PA). This PA rate was normal, on average, for the entire patient group but was greater in patients with more consistent SA responses. The PA findings were related to the Kd value obtained in binding studies with 3H-yohimbine, but not with the number of alpha 2-receptor sites. Studies on Tx production (assessed by radioimmunoassay of TxB2) showed that the ability to synthesize Tx from arachidonate was not impaired in delta-SPD, and that there was an absolute positive correlation between epinephrine-induced SA and Tx production. Aggregation in delta-SPD platelets in response to the Tx receptor agonist U44069 was consistently decreased, but could be corrected by addition of ADP. The results of the study suggest that dense granule-derived ADP is not required for PA by epinephrine, but mediates SA as a synergistic agonist with TxA2. This role of ADP in SA may be elucidated more precisely by further studies on platelet activation processes in delta-SPD.

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