Occlusive thrombi arise in mammals but not birds in response to arterial injury: evolutionary insight into human cardiovascular disease

Schmaier, Alec A.; Stalker, Timothy J.; Runge, Jeffrey J.; Lee, Dong Hoon; Nagaswami, Chandrasekaran; Mericko, Patricia; Chen, Mei; Cliché, Simon; Gariépy, C.; Brass, Lawrence F.; Hammer, Daniel A.; Weisel, John W.; Rosenthal, Karen L.; Kahn, Mark L.

doi:10.1182/blood-2011-02-338244

Cited by 63 publications

(49 citation statements)

References 36 publications

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“…To our knowledge however, the densities of αIIbβ3 receptors in monotreme and marsupial platelets have not been reported, and so it remains possible that placental birth selected for high receptor density. For comparison, the density of αIIbβ3 receptors on chicken thrombocytes has been reported to be only ∼5% of that of human platelets (78). Because humans increasingly mate with individuals outside their kinship, heterozygous deleterious variants are likely to continue to accumulate.…”

Section: Discussionmentioning

confidence: 99%

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αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia

Buitrago

Rendon²,

Liang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Next-generation sequencing is transforming our understanding of human genetic variation but assessing the functional impact of novel variants presents challenges. We analyzed missense variants in the integrin αIIbβ3 receptor subunit genes ITGA2B and ITGB3 identified by whole-exome or -genome sequencing in the ThromboGenomics project, comprising ∼32,000 alleles from 16,108 individuals. We analyzed the results in comparison with 111 missense variants in these genes previously reported as being associated with Glanzmann thrombasthenia (GT), 20 associated with alloimmune thrombocytopenia, and 5 associated with aniso/macrothrombocytopenia. We identified 114 novel missense variants in ITGA2B (affecting ∼11% of the amino acids) and 68 novel missense variants in ITGB3 (affecting ∼9% of the amino acids). Of the variants, 96% had minor allele frequencies (MAF) < 0.1%, indicating their rarity. Based on sequence conservation, MAF, and location on a complete model of αIIbβ3, we selected three novel variants that affect amino acids previously associated with GT for expression in HEK293 cells. αIIb P176H and β3 C547G severely reduced αIIbβ3 expression, whereas αIIb P943A partially reduced αIIbβ3 expression and had no effect on fibrinogen binding. We used receiver operating characteristic curves of combined annotationdependent depletion, Polyphen 2-HDIV, and sorting intolerant from tolerant to estimate the percentage of novel variants likely to be deleterious. At optimal cut-off values, which had 69-98% sensitivity in detecting GT mutations, between 27% and 71% of the novel αIIb or β3 missense variants were predicted to be deleterious. Our data have implications for understanding the evolutionary pressure on αIIbβ3 and highlight the challenges in predicting the clinical significance of novel missense variants.Glanzmann | integrin | single-nucleotide variants | next-generation sequencing | molecular modeling

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Section: Discussionmentioning

confidence: 99%

“…Missing segments of the αIIb calf-2 domain (amino acid residues 763-775 and 839-874), the β3 hybrid domain (amino acids residues [74][75][76][77][78][79], and the link between the EGF-1 and EGF-2 domains (amino acids residues 476-483) were built ab initio using Rosetta 2.2 (88) (Movie S1).…”

Section: Analysis Of Missense Variantsmentioning

confidence: 99%

αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia

Buitrago

Rendon²,

Liang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…Subsequently, these three haemostatic responses enhance each other, resulting in thrombus formation. In contrast, thrombus formation rarely occurs at injury sites in birds because those three responses are less efficient than the mammalian haemostatic responses 32 . Therefore, ticks of the genus Ornithodoros prevent vasoconstriction at the feeding site on host mammals by injecting TAM and thus can overcome their haemostatic systems.…”

Section: Python Molurus Adm-5mentioning

confidence: 99%

Horizontal gene transfer of a vertebrate vasodilatory hormone into ticks

Iwanaga

Isawa

2014

Nat Commun

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“…However, budgerigars have also been employed in an in vivo thrombosis experiment comparing the nature of thrombi formation with the mouse. 137 In this experiment, the comparison between the mouse, representing a mammalian species, and the budgerigar, an avian model, was investigated on the basis that these 2 divergent species had similar carotid artery size and blood flow. It was found that carotid artery wall injury resulted in vaso-occlusive thrombosis in mice but not in budgerigars.…”

Section: Psittacine Birdsmentioning

confidence: 99%

Atherosclerosis: Comparative Pathogenesis, Lipoprotein Metabolism, and Avian and Exotic Companion Mammal Models

Beaufrère

2013

Journal of Exotic Pet Medicine

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Occlusive thrombi arise in mammals but not birds in response to arterial injury: evolutionary insight into human cardiovascular disease

Cited by 63 publications

References 36 publications

αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia

αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia

Horizontal gene transfer of a vertebrate vasodilatory hormone into ticks

Atherosclerosis: Comparative Pathogenesis, Lipoprotein Metabolism, and Avian and Exotic Companion Mammal Models

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