A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease–like 2

Holmes, Susan E.; O’Hearn, Elizabeth; Rosenblatt, Adam; Callahan, Colleen; Hwang, Hyon S.; Ingersoll-Ashworth, Roxann G.; Fleisher, Adam; Stevanin, Giovanni; Brice, Alexis; Potter, Nicholas; Ross, Christopher A.; Margolis, Russell L.

doi:10.1038/ng760

Cited by 262 publications

(182 citation statements)

References 9 publications

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“…37,38 As such, HTT gene expansion in these patients will be negative. 39 Furthermore, the considerable clinical overlap between HD and dentatorubral-pallidoluysian atrophy may warrant a recommendation of ATN1 gene testing in those patients referred with a clinical diagnosis of HD who subsequently test negative for the expansion.…”

Section: Interpretationsmentioning

confidence: 99%

American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, 2014 edition: technical standards and guidelines for Huntington disease

Bean

Bayrak-Toydemir

2014

Genetics in Medicine

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Section: Interpretationsmentioning

confidence: 99%

American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, 2014 edition: technical standards and guidelines for Huntington disease

Bean

Bayrak-Toydemir

2014

Genetics in Medicine

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“…The insertions of triplet repeats in the JP-3 locus result in a human genetic disease called HDL2, with clinical symptoms similar to those of Huntington's disease (23). Although HDL2 bears the features of polyglutamine diseases, the triplet repeats do not encode polyglutamine and seem to simply disrupt the JP-3 gene.…”

Section: Discussionmentioning

confidence: 99%

Functional uncoupling between Ca ²⁺ release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins

Moriguchi

Nishi

Komazaki

et al. 2006

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

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Junctional membrane complexes (JMCs) composed of the plasma membrane and endoplasmic͞sarcoplasmic reticulum seem to be a structural platform for channel crosstalk. Junctophilins (JPs) contribute to JMC formation by spanning the sarcoplasmic reticulum membrane and binding with the plasma membrane in muscle cells. In this article, we report that mutant JP double-knockout (JP-DKO) mice lacking neural JP subtypes exhibited an irregular hindlimb reflex and impaired memory. Electrophysiological experiments indicated that the activation of small-conductance Ca 2؉ -activated K ؉ channels responsible for afterhyperpolarization in hippocampal neurons requires endoplasmic reticulum Ca 2؉ release through ryanodine receptors, triggered by NMDA receptor-mediated Ca 2؉ influx. We propose that in JP-DKO neurons lacking afterhyperpolarization, the functional communications between NMDA receptors, ryanodine receptors, and small-conductance Ca 2؉ -activated K ؉ channels are disconnected because of JMC disassembly. Moreover, JP-DKO neurons showed an impaired long-term potentiation and hyperactivation of Ca 2؉ ͞calmodulin-dependent protein kinase II. Therefore, JPs seem to have an essential role in neural excitability fundamental to plasticity and integrated functions.hippocampus ͉ learning and memory ͉ long-term potentiation ͉ ryanodine receptor ͉ SK channel F unctional communication between cell-surface and intracellular channels is an essential feature of excitable cells (1). During initiation of contraction in striated muscle cells, the activation of cell-surface dihydropyridine receptor (DHPRs) channels opens ryanodine receptors (RyRs) and triggers Ca 2ϩ release from the sarcoplasmic reticulum via either the ''Ca 2ϩ -induced Ca 2ϩ release'' or the ''voltage-induced Ca 2ϩ release'' mechanism (2). The functional couplings between the channels take place in junctional membrane complexes (JMCs), designated as the ''triad junction'' in skeletal muscle, ''diad'' in cardiac muscle, and ''peripheral coupling'' in immature striated and smooth muscles (3, 4). Recent studies indicated that junctophilin (JP) subtypes, namely JP-1-JP-4, contribute to JMC formation in muscle cells (5, 6). In JP-1 knockout mice with perinatal lethality, mutant skeletal muscle shows deficiency of triad junctions and insufficient contraction probably caused by impaired communication between DHPRs and RyRs (7). In JP-2 knockout embryos showing cardiac arrest, mutant cardiac myocytes exhibit deficiency of peripheral couplings and arrhythmic Ca 2ϩ signaling probably caused by functional uncoupling between DHPRs and RyRs (5). In the brain, both JP-3 and JP-4 are expressed in similar discrete neuronal sites and may collaboratively contribute to JMC formation (8, 9). However, the role of neural JP subtypes is largely unknown. Using knockout mice lacking both JP-3 and JP-4 (JP-DKO mice), we report their essential contributions to the tuning of excitability and plasticity in hippocampal pyramidal neurons. ResultsGeneration of JP-DKO Mice Bearing Lethality. JP-4 knockou...

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“…These studies present a strong case that JP-2 is an important component to maintain the morphological integrity of the dyad for establishing efficient E-C coupling in cardiac muscle, and that disruption of junctophilin function can result in severe pathology. This is the case beyond the cardiovascular system, as several mutations in JP-3 have been linked to the development of Huntington's Disease type 2 [44][45][46].…”

Section: Junctophilins Span the Cytoplasmic Space In Junctions To Linmentioning

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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A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease–like 2

Cited by 262 publications

References 9 publications

American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, 2014 edition: technical standards and guidelines for Huntington disease

American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, 2014 edition: technical standards and guidelines for Huntington disease

Functional uncoupling between Ca ²⁺ release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins

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

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A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease–like 2

Cited by 262 publications

References 9 publications

American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, 2014 edition: technical standards and guidelines for Huntington disease

American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, 2014 edition: technical standards and guidelines for Huntington disease

Functional uncoupling between Ca 2+ release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins

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

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Functional uncoupling between Ca ²⁺ release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins