Heart rhythm : the official journal of the Heart Rhythm Society, Sep 10, 2016
Human ANK2 loss-of-function variants are directly linked with arrhythmia phenotypes. However, in ... more Human ANK2 loss-of-function variants are directly linked with arrhythmia phenotypes. However, in atypical non-ion channel arrhythmia genes such as ANK2 (ankyrin-B) that lack the same degree of robust structure/function and clinical data, it may be more difficult to assign variant disease risk based simply on variant location, minor allele frequency, and/or predictive structural algorithms. The human ankyrin-B p.L1622I variant found in arrhythmia probands displays significant diversity in minor allele frequency across populations. The objective of this study was to directly test the in vivo impact of ankyrin-B p.L1622I on cardiac electrical phenotypes and arrhythmia risk utilizing a new animal model. We tested arrhythmia phenotypes in a new 'knock-in' animal model harboring the human ankyrin-B p.L1622I variant. Ankyrin-B p.L1622I displays reduced post-translational expression in vivo, resulting in reduced cardiac ankyrin-B expression and reduced association with binding-partn...
The Journal of clinical investigation, Jan 13, 2015
Rare functional variants of ankyrin-B have been implicated in human disease, including hereditary... more Rare functional variants of ankyrin-B have been implicated in human disease, including hereditary cardiac arrhythmia and type 2 diabetes (T2D). Here, we developed murine models to evaluate the metabolic consequences of these alterations in vivo. Specifically, we generated knockin mice that express either the human ankyrin-B variant R1788W, which is present in 0.3% of North Americans of mixed European descent and is associated with T2D, or L1622I, which is present in 7.5% of African Americans. Young AnkbR1788W/R1788W mice displayed primary pancreatic β cell insufficiency that was characterized by reduced insulin secretion in response to muscarinic agonists, combined with increased peripheral glucose uptake and concomitantly increased plasma membrane localization of glucose transporter 4 (GLUT4) in skeletal muscle and adipocytes. In contrast, older AnkbR1788W/R1788W and AnkbL1622I/L1622I mice developed increased adiposity, a phenotype that was reproduced in cultured adipocytes, and in...
Nodes of Ranvier and axon initial segments of myelinated nerves, sites of cell-cell contact in ea... more Nodes of Ranvier and axon initial segments of myelinated nerves, sites of cell-cell contact in early embryos and epithelial cells, and neuromuscular junctions of skeletal muscle all perform physiological functions that depend on clustering of functionally related but structurally diverse ion transporters and cell adhesion molecules within microdomains of the plasma membrane. These specialized cell surface domains appeared at different times in metazoan evolution, involve a variety of cell types, and are populated by distinct membrane-spanning proteins. Nevertheless, recent work has shown that these domains all share on their cytoplasmic surfaces a membrane skeleton comprised of members of the ankyrin and spectrin families. This review will summarize basic features of ankyrins and spectrins, and will discuss emerging evidence that these proteins are key players in a conserved mechanism responsible for assembly and maintenance of physiologically important domains on the surfaces of di...
Ankyrin and spectrin were first discovered as binding partners in the membrane skeleton of human ... more Ankyrin and spectrin were first discovered as binding partners in the membrane skeleton of human erythrocytes. Mutations in genes encoding these proteins cause hereditary spherocytosis. Recent advances reveal that ankyrin and spectrin are required for organization of a surprisingly diverse set of proteins, including ion channels and cell adhesion molecules that are localized in specialized membrane domains in many cell types. New insights into the cell biology of ankyrin and spectrin reveal that these proteins actively participate in assembly of specialized membrane domains in addition to their conventional maintenance role as scaffolding proteins. Recently described inherited human diseases due to defects in spectrin or ankyrin include spinocerebellar ataxia type 5 and a cardiac arrhythmia, termed sick sinus syndrome with bradycardia or ankyrin-B syndrome. Together, these studies identify an emerging paradigm for pathogenesis of human disease where failure in cellular localization of membrane-spanning proteins results in loss of physiological function.
Voltage-gated sodium (Nav) channels in cardiomyocytes are localized in specialized membrane domai... more Voltage-gated sodium (Nav) channels in cardiomyocytes are localized in specialized membrane domains that optimize their functions in propagating action potentials across cell junctions and in stimulating voltage-gated calcium channels located in T tubules. Mutation of the ankyrin-binding site of Nav1.5, the principal Nav channel in the heart, was previously known to cause cardiac arrhythmia and the retention of Nav1.5 in an intracellular compartment in cardiomyocytes. Conclusive evidence is now provided that direct interaction between Nav1.5 and ankyrin-G is necessary for the expression of Nav1.5 at the cardiomyocyte cell surface.
The scaffolding protein ankyrin-B is needed for maximal insulin release, and loss of function is ... more The scaffolding protein ankyrin-B is needed for maximal insulin release, and loss of function is a risk factor for diabetes.
Here we report the unexpected finding that specific human ANK2 variants represent a new example o... more Here we report the unexpected finding that specific human ANK2 variants represent a new example of balanced human variants. The prevalence of certain ANK2 (encodes ankyrin-B) variants range from 2 percent of European individuals to 8 percent in individuals from West Africa. Ankyrin-B variants associated with severe human arrhythmia phenotypes (eg E1425G, V1516D, R1788W) were rare in the general population. Variants associated with less severe clinical and in vitro phenotypes were unexpectedly common. Studies with the ankyrin-B +/2 mouse reveal both benefits of enhanced cardiac contractility, as well as costs in earlier senescence and reduced lifespan. Together these findings suggest a constellation of traits that we term ''ankyrin-B syndrome'', which may contribute to both aging-related disorders and enhanced cardiac function.
Heart rhythm : the official journal of the Heart Rhythm Society, Sep 10, 2016
Human ANK2 loss-of-function variants are directly linked with arrhythmia phenotypes. However, in ... more Human ANK2 loss-of-function variants are directly linked with arrhythmia phenotypes. However, in atypical non-ion channel arrhythmia genes such as ANK2 (ankyrin-B) that lack the same degree of robust structure/function and clinical data, it may be more difficult to assign variant disease risk based simply on variant location, minor allele frequency, and/or predictive structural algorithms. The human ankyrin-B p.L1622I variant found in arrhythmia probands displays significant diversity in minor allele frequency across populations. The objective of this study was to directly test the in vivo impact of ankyrin-B p.L1622I on cardiac electrical phenotypes and arrhythmia risk utilizing a new animal model. We tested arrhythmia phenotypes in a new 'knock-in' animal model harboring the human ankyrin-B p.L1622I variant. Ankyrin-B p.L1622I displays reduced post-translational expression in vivo, resulting in reduced cardiac ankyrin-B expression and reduced association with binding-partn...
The Journal of clinical investigation, Jan 13, 2015
Rare functional variants of ankyrin-B have been implicated in human disease, including hereditary... more Rare functional variants of ankyrin-B have been implicated in human disease, including hereditary cardiac arrhythmia and type 2 diabetes (T2D). Here, we developed murine models to evaluate the metabolic consequences of these alterations in vivo. Specifically, we generated knockin mice that express either the human ankyrin-B variant R1788W, which is present in 0.3% of North Americans of mixed European descent and is associated with T2D, or L1622I, which is present in 7.5% of African Americans. Young AnkbR1788W/R1788W mice displayed primary pancreatic β cell insufficiency that was characterized by reduced insulin secretion in response to muscarinic agonists, combined with increased peripheral glucose uptake and concomitantly increased plasma membrane localization of glucose transporter 4 (GLUT4) in skeletal muscle and adipocytes. In contrast, older AnkbR1788W/R1788W and AnkbL1622I/L1622I mice developed increased adiposity, a phenotype that was reproduced in cultured adipocytes, and in...
Nodes of Ranvier and axon initial segments of myelinated nerves, sites of cell-cell contact in ea... more Nodes of Ranvier and axon initial segments of myelinated nerves, sites of cell-cell contact in early embryos and epithelial cells, and neuromuscular junctions of skeletal muscle all perform physiological functions that depend on clustering of functionally related but structurally diverse ion transporters and cell adhesion molecules within microdomains of the plasma membrane. These specialized cell surface domains appeared at different times in metazoan evolution, involve a variety of cell types, and are populated by distinct membrane-spanning proteins. Nevertheless, recent work has shown that these domains all share on their cytoplasmic surfaces a membrane skeleton comprised of members of the ankyrin and spectrin families. This review will summarize basic features of ankyrins and spectrins, and will discuss emerging evidence that these proteins are key players in a conserved mechanism responsible for assembly and maintenance of physiologically important domains on the surfaces of di...
Ankyrin and spectrin were first discovered as binding partners in the membrane skeleton of human ... more Ankyrin and spectrin were first discovered as binding partners in the membrane skeleton of human erythrocytes. Mutations in genes encoding these proteins cause hereditary spherocytosis. Recent advances reveal that ankyrin and spectrin are required for organization of a surprisingly diverse set of proteins, including ion channels and cell adhesion molecules that are localized in specialized membrane domains in many cell types. New insights into the cell biology of ankyrin and spectrin reveal that these proteins actively participate in assembly of specialized membrane domains in addition to their conventional maintenance role as scaffolding proteins. Recently described inherited human diseases due to defects in spectrin or ankyrin include spinocerebellar ataxia type 5 and a cardiac arrhythmia, termed sick sinus syndrome with bradycardia or ankyrin-B syndrome. Together, these studies identify an emerging paradigm for pathogenesis of human disease where failure in cellular localization of membrane-spanning proteins results in loss of physiological function.
Voltage-gated sodium (Nav) channels in cardiomyocytes are localized in specialized membrane domai... more Voltage-gated sodium (Nav) channels in cardiomyocytes are localized in specialized membrane domains that optimize their functions in propagating action potentials across cell junctions and in stimulating voltage-gated calcium channels located in T tubules. Mutation of the ankyrin-binding site of Nav1.5, the principal Nav channel in the heart, was previously known to cause cardiac arrhythmia and the retention of Nav1.5 in an intracellular compartment in cardiomyocytes. Conclusive evidence is now provided that direct interaction between Nav1.5 and ankyrin-G is necessary for the expression of Nav1.5 at the cardiomyocyte cell surface.
The scaffolding protein ankyrin-B is needed for maximal insulin release, and loss of function is ... more The scaffolding protein ankyrin-B is needed for maximal insulin release, and loss of function is a risk factor for diabetes.
Here we report the unexpected finding that specific human ANK2 variants represent a new example o... more Here we report the unexpected finding that specific human ANK2 variants represent a new example of balanced human variants. The prevalence of certain ANK2 (encodes ankyrin-B) variants range from 2 percent of European individuals to 8 percent in individuals from West Africa. Ankyrin-B variants associated with severe human arrhythmia phenotypes (eg E1425G, V1516D, R1788W) were rare in the general population. Variants associated with less severe clinical and in vitro phenotypes were unexpectedly common. Studies with the ankyrin-B +/2 mouse reveal both benefits of enhanced cardiac contractility, as well as costs in earlier senescence and reduced lifespan. Together these findings suggest a constellation of traits that we term ''ankyrin-B syndrome'', which may contribute to both aging-related disorders and enhanced cardiac function.
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Papers by Jane Healy