Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans

Landstrom, Andrew P.; Weisleder, Noah; Batalden, Karin B.; Bos, J. Martijn; Tester, David J.; Ommen, Steve R.; Wehrens, Xander H.T.; Claycomb, William C.; Ko, Jae Kyun; Hwang, Moonsun; Pan, Zui; Ma, Jianjie; Ackerman, Michael J.

doi:10.1016/j.yjmcc.2007.04.006

Cited by 165 publications

(173 citation statements)

References 51 publications

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“…There are several other disease genes for HCM, including mutations in caveolin-3 gene (CAV3), 40 meta-vinculin gene (VCL), 41 aB-crystallin gene (CRYAB), 42 junctophilin-2 gene (JPH-2), 43 obscurin gene (OBSCN) 44 and most recently reported CARP gene (ANKRD1) 45 ( Figure 2). Functional analyses were reported for CRYAB, CAV3, OBSCN and ANKRD1 mutations; aggregation of aB-crystalline in cytoplasm, 42 decreased cell surface expression of caveolin-3, 40 decreased binding to titin, 44 and increased binding to titin and myopalladin, 45 respectively.…”

Section: Other Mutations In Hcmmentioning

confidence: 99%

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Kimura

2010

J Hum Genet

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Cardiomyopathy is caused by functional abnormality of cardiac muscle. The functional abnormality involved in its etiology includes both extrinsic and intrinsic factors, and cardiomyopathy caused by the intrinsic factors is called as idiopathic or primary cardiomyopathy. There are several clinical types of primary cardiomyopathy including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Linkage studies and candidate gene approaches have explored the disease genes for hereditary primary cardiomyopathy. The most notable finding was that mutations in the same disease gene can be found in different clinical types of cardiomyopathy. Functional analyses of disease-related mutations have revealed that characteristic functional alterations are associated with the clinical types, such that increased and decreased Ca 2+ sensitivity due to sarcomere mutations are associated with HCM and DCM, respectively. In addition, our recent studies have suggested that mutations in the Z-disc components found in HCM and DCM may result in increased and decreased stiffness of sarcomere; that is, stiff sarcomere and loose sarcomere, respectively, and hence altered stretch response. More recently, mutations in the components of I region were found in hereditary cardiomyopathy and the functional analyses of the mutations suggested that the altered stress response was associated with cardiomyopathy, further complicating the etiology and pathogenesis. However, elucidation of genetic etiology and functional alterations caused by the mutations shed lights on the new therapeutic approaches to hereditary cardiomyopathy, such that treatment of DCM with a Ca 2+ sensitizer prevented the disease in a mouse model.

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Section: Other Mutations In Hcmmentioning

confidence: 99%

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Kimura

2010

J Hum Genet

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“…Recent studies have identified mutations in the human JP-2 gene that lead to hypertrophic cardiomyopathy (HCM) and consequences in cellular Ca 2+ handling [40]. Other JP-2 mutations in a separate cohort suggest that polymorphisms in the JP-2 gene that link to HCM may be common in various populations [41].…”

Section: Junctophilins Span the Cytoplasmic Space In Junctions To Linmentioning

confidence: 99%

“…Mutations have been identified in JP-2 (arrows) that are linked to hypertrophic cardiomyopathy in different studies (Ref. [40] in black; Ref. [41] in blue).…”

Section: Importance Of Tric In Physiology and Pathophysiologymentioning

confidence: 99%

Immuno-proteomic approach to excitation–contraction coupling in skeletal and cardiac muscle: Molecular insights revealed by the mitsugumins

Weisleder

Takeshima

2008

Cell Calcium

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A comprehensive understanding of excitation-contraction (E-C) coupling in skeletal and cardiac muscle requires that all the major components of the Ca 2+ release machinery be resolved. We utilized a unique immuno-proteomic approach to generate a monoclonal antibody library that targets proteins localized to the skeletal muscle triad junction, which provides a structural context to allow efficient E-C coupling. Screening of this library has identified several mitsugumins (MG); proteins that can be localized to the triad junction in mammalian skeletal muscle. Many of these proteins, including MG29 and junctophilin, are important components in maintaining the structural integrity of the triad junction. Other triad proteins, such as calumin, play a more direct role in regulation of muscle Ca 2+ homeostasis. We have recently identified a family of trimeric intracellular cation-selective (TRIC) channels that allow for K + movement into the endoplasmic or sarcoplasmic reticulum to counter a portion of the transient negative charge produced by Ca 2+ release into the cytosol. Further study of TRIC channel function and other novel mitsugumins will increase our understanding of E-C coupling and Ca 2+ homoeostasis in muscle physiology and pathophysiology.

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“…The mouse has become a mainstay of understanding mammalian gene function and modeling human disease (Kohl et al, 2007;Landstrom et al, 2007;Matera et al, 2007;Tsukumo et al, 2007). An increasing number of studies have taken advantage of microCT for their phenotypic characterizations of adult mouse skeletal morphology (Nieman et al, 2006;Perlyn et al, 2006;Nahrendorf et al, 2007), but fetal skeletal analysis remains challenging (Kindlmann et al, 2004).…”

Section: Rapid Microct Scans Of Mouse Fetal Skeletons Closely Approximentioning

confidence: 99%

Optimization of Volumetric Computed Tomography for Skeletal Analysis of Model Genetic Organisms

Vasquez

Hansen

Bahadur

et al. 2008

The Anatomical Record

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Forward and reverse genetics now allow researchers to understand embryonic and postnatal gene function in a broad range of species. Although some genetic mutations cause obvious morphological change, other mutations can be more subtle and, without adequate observation and quantification, might be overlooked. For the increasing number of genetic model organisms examined by the growing field of phenomics, standardized but sensitive methods for quantitative analysis need to be incorporated into routine practice to effectively acquire and analyze ever-increasing quantities of phenotypic data. In this study, we present platform-independent parameters for the use of microscopic x-ray computed tomography (microCT) for phenotyping species-specific skeletal morphology of a variety of different genetic model organisms. We show that microCT is suitable for phenotypic characterization for prenatal and postnatal specimens across multiple species.

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Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans

Cited by 165 publications

References 51 publications

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Immuno-proteomic approach to excitation–contraction coupling in skeletal and cardiac muscle: Molecular insights revealed by the mitsugumins

Optimization of Volumetric Computed Tomography for Skeletal Analysis of Model Genetic Organisms

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