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<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="fjxdVOX8R1uDQSk4Rzuqcb66KP54JmdGw6hiyEqurCh7KjqUuS7sGjCKiTNgCXL0">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="fjxdVOX8R1uDQSk4Rzuqcb66KP54JmdGw6hiyEqurCh7KjqUuS7sGjCKiTNgCXL0">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="fjxdVOX8R1uDQSk4Rzuqcb66KP54JmdGw6hiyEqurCh7KjqUuS7sGjCKiTNgCXL0">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="fjxdVOX8R1uDQSk4Rzuqcb66KP54JmdGw6hiyEqurCh7KjqUuS7sGjCKiTNgCXL0">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="fjxdVOX8R1uDQSk4Rzuqcb66KP54JmdGw6hiyEqurCh7KjqUuS7sGjCKiTNgCXL0">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="15863612">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://www.pnas.org/doi/10.1073/pnas.0502506102?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub 0pubmed"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=4487&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=15863612&amp;db=pubmed&amp;nlmid=7505876"
title="See full text options at Atypon"
data-ga-category="full_text"
data-ga-action="Atypon"
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><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--pnas.org-pb-assets-images-pubmed-pnas-pubmed-fulltext.png" alt="Atypon full text link"><span class="text">
Atypon
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/15863612/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=15863612&amp;db=pubmed&amp;nlmid=7505876"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="15863612"
><span class="text">
Free PMC article
</span></a>
</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/15863612/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/15863612/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="15863612" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F15863612%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="fjxdVOX8R1uDQSk4Rzuqcb66KP54JmdGw6hiyEqurCh7KjqUuS7sGjCKiTNgCXL0"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
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Timothy syndrome (TS) is a multisystem disorder that causes syncope and sudden death from cardiac arrhythmias. Prominent features include congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. All TS individuals have syndactyly (webbing of fingers and toes). We discovered that TS resulted from a recurrent, de novo cardiac L-type calcium channel (CaV1.2) mutation, G406R. G406 is located in alternatively spliced exon 8A, encoding transmembrane segment S6 of domain I. Here, we describe two individuals with a severe variant of TS (TS2). Neither child had syndactyly. Both individuals had extreme prolongation of the QT interval on electrocardiogram, with a QT interval corrected for heart rate ranging from 620 to 730 ms, causing multiple arrhythmias and sudden death. One individual had severe mental retardation and nemaline rod skeletal myopathy. We identified de novo missense mutations in exon 8 of CaV1.2 in both individuals. One was an analogous mutation to that found in exon 8A in classic TS, G406R. The other mutation was G402S. Exon 8 encodes the same region as exon 8A, and the two are mutually exclusive. The spliced form of CaV1.2 containing exon 8 is highly expressed in heart and brain, accounting for approximately 80% of CaV1.2 mRNAs. G406R and G402S cause reduced channel inactivation, resulting in maintained depolarizing L-type calcium currents. Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase risk of arrhythmia. These data indicate that gain-of-function mutations of CaV1.2 exons 8 and 8A cause distinct forms of TS.
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<strong class="figure-label">
<p> Fig. 1. </p>
</strong>
<div class="figure-caption-contents"><p> Dysmorphic facial features, marked QT… </p></div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 1. </p>
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<div class="figure-caption-contents"><p> Dysmorphic facial features, marked QT interval prolongation, arrhythmia, and skeletal muscle defects in… </p></div>
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Fig. 1.
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<div class="figure-caption-contents">Dysmorphic facial features, marked QT interval prolongation, arrhythmia, and skeletal muscle defects in affected individuals. (<i>A</i><i>C</i>) Individual 1 exhibiting dysmorphic facial features including flat nasal bridge, thin upper lip, and protruding tongue. (<i>D</i>) Electrocardiogram shows severe QT interval prolongation, causing 2:1 atrio-ventricular block seen as two atrial beats (P-waves) for each ventricular beat (QRS complex). (<i>E</i>) Electrocardiogram shows polymorphic ventricular tachycardia for individual 1. (<i>F</i>) Frozen section of left quadriceps biopsy stained with modified Gomori trichrome showing rare nemaline rods (indicated by arrows) in scattered myofibers (scale bar, 20 μm). (<i>G</i>) Electron micrograph of subsarcolemmal collections of electron dense rods (×17,800). (<i>H</i>) Electron micrograph illustrating normal sarcomeric architecture for comparison with <i>G</i> (×17,800).</div>
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data-pmc-id="PMC1149428"
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<img class="figure-thumb" itemprop="thumbnail"
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<strong class="figure-label">
<p> Fig. 2. </p>
</strong>
<div class="figure-caption-contents"><i> De novo </i> Ca <sub> v </sub> 1.2…</div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 2. </p>
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<div class="figure-caption-contents"><i> De novo </i> Ca <sub> v </sub> 1.2 mutations cause TS2. ( <i> A </i> ) Pedigree shows…</div>
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Fig. 2.
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<div class="figure-caption-contents"><i>De novo</i> Ca<sub>v</sub>1.2 mutations cause TS2. (<i>A</i>) Pedigree shows sporadic occurrence of the disease phenotype and <i>de novo</i> G1216A missense mutation in individual 1. This mutation leads to the substitution of glycine 406 with arginine (G406R) in exon 8. Circles and squares indicate females and males, respectively. Filled and empty symbols denote affected and unaffected individuals, respectively. The individual with a slash is deceased. Sequence tracings were derived from blood DNA samples unless otherwise indicated. (<i>B</i>) Pedigree shows sporadic occurrence of the disease phenotype and <i>de novo</i> G1204A missense mutation in individual 2. This mutation leads to the substitution of glycine 402 with serine (G402S) in exon 8. The mutant peak (green, arrow) is present in sequence from blood DNA but only a small peak is detected in oral mucosa DNA, indicating mosaicism. Mosaicism may explain the milder phenotype in this individual. (<i>C</i>) Amino acid sequence alignment showing conservation of glycine at positions 402 and 406 from multiple species. Bracket indicates the end of the sixth transmembrane segment of domain I (DI/S6). (<i>D</i>)(<i>Upper</i>) Predicted topology of Ca<sub>V</sub>1.2, showing the location of the mutations. (<i>Lower</i>) Homology of the amino acid sequence of exons 8 and 8A. DI/S6 is underlined. G402 and G406, the amino acids mutated in TS2, are both in exon 8 and are shown in red. G406, mutated in TS, is in exon 8A and is shown in blue. These data indicate that <i>de novo</i> missense mutations in Ca<sub>V</sub>1.2 exon 8 cause severe long QT syndrome and other phenotypic abnormalities.</div>
</figcaption>
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<figure class="figure-item "
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href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf49/1149428/3df14050cf21/zpq0190582390003.jpg"
itemprop="contentUrl"
aria-describedby="figure-caption-2"
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data-image-alt="Fig. 3."
data-pmc-id="PMC1149428"
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<img class="figure-thumb" itemprop="thumbnail"
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf49/1149428/e721aa5b3528/zpq0190582390003.gif"
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<div class="caption-wrap">
<strong class="figure-label">
<p> Fig. 3. </p>
</strong>
<div class="figure-caption-contents"><p> The Ca <sub> V </sub> 1.2 exon… </p></div>
</div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 3. </p>
</strong>
<div class="figure-caption-contents"><p> The Ca <sub> V </sub> 1.2 exon 8 splice variant is highly expressed in heart… </p></div>
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<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 3.
</strong>
<div class="figure-caption-contents">The Ca<sub>V</sub>1.2 exon 8 splice variant is highly expressed in heart and brain. (<i>A</i>) Human Northern blot analyses show expression of Ca<sub>V</sub>1.2 exon 8 in brain, heart, and other tissues. (<i>B</i>) mRNA dot blot demonstrates expression of Ca<sub>V</sub>1.2 exon 8 in multiple fetal and adult tissues, including many regions of the brain.</div>
</figcaption>
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data-pmc-id="PMC1149428"
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<img class="figure-thumb" itemprop="thumbnail"
id="article-image-3"
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<strong class="figure-label">
<p> Fig. 4. </p>
</strong>
<div class="figure-caption-contents"><p> Mutations of Ca <sub> V </sub> 1.2… </p></div>
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</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 4. </p>
</strong>
<div class="figure-caption-contents"><p> Mutations of Ca <sub> V </sub> 1.2 exon 8 cause nearly complete absence of voltage-dependent… </p></div>
</div>
<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 4.
</strong>
<div class="figure-caption-contents">Mutations of Ca<sub>V</sub>1.2 exon 8 cause nearly complete absence of voltage-dependent channel inactivation. (<i>A</i><i>C</i>) WT (<i>A</i>), G402S (<i>B</i>), and G406R (<i>C</i>) Ca<sub>V</sub>1.2 channel currents were recorded from <i>Xenopus</i> oocytes in response to voltage pulses applied in 10-mV increments from -70 to +40 mV, second pulse to +10 mV. External solution contained 40 mM BaCl<sub>2</sub> to eliminate Ca<sup>2+</sup>-dependent inactivation of Ca<sub>V</sub>1.2 channels. Note the lack of current inactivation for mutant channels compared with WT channel currents. (<i>D</i>) G406R channels have similar Ba<sup>2+</sup> currentvoltage (<i>IV</i>) relationship compared with WT. (<i>E</i>) Voltage dependence of Ba<sup>2+</sup> current activation for WT (<i>V</i><sub>1/2</sub> = 4.5 ± 0.1 mV; <i>k</i> = 5.5 ± 0.1 mV; <i>n</i> = 7), G402S (<i>V</i><sub>1/2</sub> = 6.2 ± 0.1 mV; <i>k</i> = 7.5 ± 0.1 mV; <i>n</i> = 14), and G406R (<i>V</i><sub>1/2</sub> = -4.4 ± 0.3 mV; <i>k</i> = 5.4 ± 0.2 mV; <i>n</i> = 14). (<i>F</i>) Voltage dependence of Ba<sup>2+</sup> current inactivation for WT (<i>V</i><sub>1/2</sub> = -6.6 ± 0.4 mV; k = 7.6 ± 0.4 mV; <i>n</i> = 8) and mutant Ca<sub>V</sub>1.2 channels. The minimum value for relative inactivation was 0.10 ± 0.01 for WT (<i>n</i> = 8), but 0.88 ± 0.03 for G406R (<i>n</i> = 15) and 0.91 ± 0.04 for G402S (<i>n</i> = 6), indicating nearly complete absence of voltage dependence of inactivation.</div>
</figcaption>
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href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf49/1149428/e35052c8a04b/zpq0190582390005.jpg"
itemprop="contentUrl"
aria-describedby="figure-caption-4"
role="button"
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data-image-alt="Fig. 5."
data-pmc-id="PMC1149428"
data-figure-id="fig5">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-4"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf49/1149428/503c757f5520/zpq0190582390005.gif"
alt="Fig. 5." />
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<strong class="figure-label">
<p> Fig. 5. </p>
</strong>
<div class="figure-caption-contents"><p> Glycine is a critical amino… </p></div>
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</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 5. </p>
</strong>
<div class="figure-caption-contents"><p> Glycine is a critical amino acid at position 406 of Ca <sub> V </sub> 1.2.… </p></div>
</div>
<figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 5.
</strong>
<div class="figure-caption-contents">Glycine is a critical amino acid at position 406 of Ca<sub>V</sub>1.2. Voltage dependence of inactivation for WT and mutant exon 8 Ca<sub>v</sub>1.2 channels were determined in <i>Xenopus</i> oocytes by measuring the peak amplitude of current evoked during a pulse to +10 mV that followed a 2-s conditioning pulse applied to a variable potential. Currents were normalized and plotted as a function of the conditioning potential. External solution contained 40 mM BaCl<sub>2</sub> to eliminate Ca<sup>2+</sup>-dependent inactivation. WT, <i>n</i> = 6; G406R, <i>n</i> = 10; G406E, <i>n</i> = 11; G406K, <i>n</i> = 9; G406P, <i>n</i> = 8; G406S, <i>n</i> = 8; G406V, <i>n</i> = 6; G406A, <i>n</i> = 11.</div>
</figcaption>
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itemprop="contentUrl"
aria-describedby="figure-caption-5"
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data-image-alt="Fig. 6."
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<img class="figure-thumb" itemprop="thumbnail"
id="article-image-5"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf49/1149428/251ececea9c4/zpq0190582390006.gif"
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<strong class="figure-label">
<p> Fig. 6. </p>
</strong>
<div class="figure-caption-contents"><p> Computer modeling revealed prolonged action… </p></div>
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</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 6. </p>
</strong>
<div class="figure-caption-contents"><p> Computer modeling revealed prolonged action potentials, altered intracellular calcium handling, and DADs induced… </p></div>
</div>
<figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 6.
</strong>
<div class="figure-caption-contents">Computer modeling revealed prolonged action potentials, altered intracellular calcium handling, and DADs induced by Ca<sub>V</sub>1.2 mutations. (<i>A</i>) Simulated voltage dependence of L-type calcium channel current inactivation for WT (black), G406R (green), WT/exon 8 G406R heterozygotes (red), and WT/exon 8A G406R heterozygotes (blue). The relative voltage-dependent inactivation was plotted as a function of <i>V</i><sub>m</sub>. (<i>B</i>) Intracellular calcium transients during a simulated action potential. The peak of the transient was increased by 29% in WT/exon 8 G406R heterozygotes compared with 7% in WT/exon 8A G406R, because the exon 8 splice variant expression was assumed to predominate in the heart with a ratio ≈3.5:1. (<i>C</i>) Cardiac action potentials were prolonged by 30% in WT/exon 8 G406R compared with 8% prolongation in WT/exon 8A G406R heterozygotes. (<i>D</i><i>F</i>) Transients of [Ca<sup>2+</sup>]<sub>JSR</sub> (<i>D</i>), [Ca<sup>2+</sup>]<sub>i</sub> (<i>E</i>), and <i>V</i><sub>m</sub> (<i>F</i>) were calculated for a stimulus frequency of 3 Hz. The last three action potentials of 3-Hz pacing were followed by a pause. During this pause, exon WT/exon 8A G406R led to a DAD after 509 ms with a peak voltage of -54 mV; WT/exon 8 G406R led to a triggered action potential after 423 ms with a peak voltage of 26 mV. In this model, DADs result from spontaneous release of Ca<sup>2+</sup> from the sarcoplasmic reticulum. Experimental studies of cardiac myocytes have shown that DADs result from Ca<sub>i</sub> overload and subsequent activation of the Na/Ca exchanger, and to a lesser extent, a Ca<sub>i</sub>-activated cation-nonselective conductance and a Ca<sub>i</sub>-activated Cl<sup>-</sup> conductance (25).</div>
</figcaption>
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<figure class="figure-item tail"
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<img class="figure-thumb" itemprop="thumbnail"
id="article-image-6"
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<strong class="figure-label">
<p> Fig. 7. </p>
</strong>
<div class="figure-caption-contents"><p> Transient changes in stimulation frequency… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 7. </p>
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<div class="figure-caption-contents"><p> Transient changes in stimulation frequency lead to electrophysiological instabilities in myocytes harboring Ca… </p></div>
</div>
<figcaption id="figure-caption-6" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 7.
</strong>
<div class="figure-caption-contents">Transient changes in stimulation frequency lead to electrophysiological instabilities in myocytes harboring Ca<sub>V</sub>1.2 channel mutations. In this simulation, the stimulus frequency was increased from 2.5 to 3 Hz at time 0 s. The myocyte was then stimulated at 3 Hz for a variable duration (<i>t</i>), followed by a pause. The peak values of [Ca<sup>2+</sup>]<sub>JSR</sub> (<i>A</i>), [Ca<sup>2+</sup>]<sub>i</sub> (<i>B</i>), and V<sub>m</sub> (<i>C</i>) as well as the start time of spontaneous calcium release (<i>D</i>) were determined during the pause. The start time is specified relative to the time of the last stimulus. In the transitional phase, myocytes with WT/exon 8A G406R Ca<sub>V</sub>1.2 showed subthreshold DADs between <i>t</i> = 9 and 77 s. With longer times (<i>t</i> &gt;77 s) the DAD triggered an action potential. Myocytes with WT/exon 8 G406R Ca<sub>V</sub>1.2 also exhibited DADs, which were sporadic for <i>t</i> &lt;82 s. Only some of these DADs triggered action potentials (e.g., at <i>t</i> = 67 s). WT myocytes never showed DADs. Together, these simulations predict that the Ca<sub>V</sub>1.2 mutations promote electrophysiological instability that could induce lethal arrhythmia in response to relatively minor changes in heart rate.</div>
</figcaption>
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<div id="substances" class="substances keywords-section">
<h2 class="title">
Substances
</h2>
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<div id="related-links" class="related-links">
<h2 class="title">
Related information
</h2>
<ul class="related-links-list"><li><a title="PubMed links associated with Books" href="https://www.ncbi.nlm.nih.gov/books?linkname=pubmed_books_refs&amp;from_uid=15863612"
ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=15863612&ordinalpos=1&linkpos=1">
Cited in Books
</a></li><li><a title="Clinical variations associated with publication" href="https://www.ncbi.nlm.nih.gov/clinvar?linkname=pubmed_clinvar&amp;from_uid=15863612"
ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=15863612&ordinalpos=1&linkpos=2">
ClinVar
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ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=15863612&ordinalpos=1&linkpos=3">
Gene
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ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=15863612&ordinalpos=1&linkpos=4">
Gene (GeneRIF)
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ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=15863612&ordinalpos=1&linkpos=5">
MedGen
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ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=15863612&ordinalpos=1&linkpos=6">
MedGen (Bookshelf cited)
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ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=15863612&ordinalpos=1&linkpos=7">
MedGen (OMIM)
</a></li><li><a title="OMIM (cited) Links" href="https://www.ncbi.nlm.nih.gov/omim?linkname=pubmed_omim_cited&amp;from_uid=15863612"
ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=15863612&ordinalpos=1&linkpos=8">
OMIM (cited)
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ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=15863612&ordinalpos=1&linkpos=9">
Protein
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ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=15863612&ordinalpos=1&linkpos=10">
Protein (RefSeq)
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ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=15863612&ordinalpos=1&linkpos=11">
PubChem Compound (MeSH Keyword)
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SNP
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</div>
<div id="grants" class="grants">
<h2 class="title">
Grants and funding
</h2>
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<div id="linkout" class="linkout">
<h2 class="title">
LinkOut - more resources
</h2>
<ul class="linkout-list"><li><h3 class="linkout-category">Full Text Sources</h3><ul class="linkout-category-links"><li><a
href="https://www.pnas.org/doi/10.1073/pnas.0502506102?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub 0pubmed"
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PubMed Central
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