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<div class="action-panel-control-wrap">
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To:
</label>
<input type="email" aria-label="Recipient Email Address" placeholder="email@example.com" id="email-to" class="email-to" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="100" required>
</div>
<div class="action-panel-control-wrap">
<label for="email-from" class="action-panel-label">
From:
</label>
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" 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>
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<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
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<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" />
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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"
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data-add-to-collection-max-amount="1000"
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<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"
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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:
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<input
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name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
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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"
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data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
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<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"
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<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>
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</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
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<form id="saved-search-action-panel-form"
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data-create-saved-search-url="/create-saved-search/"
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<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>
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<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>
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<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
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<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?
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<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
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<option value="Saturday">Saturday</option>
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<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
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<option value="MEDLINE">PubMed</option>
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<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
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Send even when there aren't any new results
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Optional text in email:
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</div>
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<button class="action-panel-submit"
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data-ga-category="save_share"
data-ga-action="alert"
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Save
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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
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</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
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Create a file for external citation management software
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<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
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</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
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Name of RSS Feed:
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class="rss-name"
value=''
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<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:
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<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
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</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
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disabled
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data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
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</form>
</div>
</div>
</div>
</div>
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<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"
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aria-label="Save article in MyNCBI collections."
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data-collections-open-dialog-enabled="false"
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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/"
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data-myncbi-max-collection-name-length="100"
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name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
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<h1 class="heading-title">
Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly
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><sup class="key">19</sup> Laboratory of embryology and genetics of human malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, 75015, France.</li>
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><sup class="key">21</sup> Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, 1105AZ, The Netherlands. c.r.bezzina@amc.uva.nl.</li>
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><sup class="key">22</sup> Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, 20892, USA. brooksb@nei.nih.gov.</li>
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Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly
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<span class="authors-list-item "><span class="full-name">Najim Lahrouchi</span><span class="citation-separator">&nbsp;et al.</span></span>
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data-ga-label="Shahida Moosa">Shahida Moosa</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Institute of Human Genetics, University Medical Center Goettingen, 37073, Goettingen, Germany." href="#short-view-affiliation-5" ref="linksrc=author_aff">
5
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Boston Children&#x27;s Hospital and Harvard Medical School, Boston, MA, 02215, USA." href="#short-view-affiliation-6" ref="linksrc=author_aff">
6
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Bharti+S&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-label="Sanita Bharti">Sanita Bharti</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, 20892, USA." href="#short-view-affiliation-2" ref="linksrc=author_aff">
2
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Unit on Ocular &amp; Stem Cell Translational Research, National Eye Institute, NIH, Bethesda, MD, 20892, USA." href="#short-view-affiliation-7" ref="linksrc=author_aff">
7
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Sharma+R&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-label="Ruchi Sharma">Ruchi Sharma</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Unit on Ocular &amp; Stem Cell Translational Research, National Eye Institute, NIH, Bethesda, MD, 20892, USA." href="#short-view-affiliation-7" ref="linksrc=author_aff">
7
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Abu-Asab+M&amp;cauthor_id=30862798"
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data-ga-label="Mones Abu-Asab">Mones Abu-Asab</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Section of Histopathology, National Eye Institute, NIH, Bethesda, MD, 20892, USA." href="#short-view-affiliation-8" ref="linksrc=author_aff">
8
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Onojafe+F&amp;cauthor_id=30862798"
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data-ga-label="Felix Onojafe">Felix Onojafe</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, 20892, USA." href="#short-view-affiliation-2" ref="linksrc=author_aff">
2
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Adadi+N&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-label="Najlae Adadi">Najlae Adadi</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Centre de Recherche en Génomique des Pathologies Humaines (GENOPATH), Faculté de Médecine et de Pharmacie, Mohammed V University of Rabat, 10100, Rabat, Morocco." href="#short-view-affiliation-3" ref="linksrc=author_aff">
3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Lodder+EM&amp;cauthor_id=30862798"
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data-ga-label="Elisabeth M Lodder">Elisabeth M Lodder</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, 1105AZ, The Netherlands." href="#short-view-affiliation-1" ref="linksrc=author_aff">
1
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Laarabi+FZ&amp;cauthor_id=30862798"
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data-ga-label="Fatima-Zahra Laarabi">Fatima-Zahra Laarabi</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Département de génétique médicale, Institut National d&#x27;Hygiène, BP 769 Agdal, 10090, Rabat, Morocco." href="#short-view-affiliation-9" ref="linksrc=author_aff">
9
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Lamsyah+Y&amp;cauthor_id=30862798"
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data-ga-label="Yassine Lamsyah">Yassine Lamsyah</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Service d&#x27;Ophtalmologie B, Hôpital des Spécialités, CHU Rabat, Faculté de médecine et de Pharmacie, Mohammed V University of Rabat, 10100, Rabat, Morocco." href="#short-view-affiliation-10" ref="linksrc=author_aff">
10
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Elorch+H&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-label="Hamza Elorch">Hamza Elorch</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Service d&#x27;Ophtalmologie B, Hôpital des Spécialités, CHU Rabat, Faculté de médecine et de Pharmacie, Mohammed V University of Rabat, 10100, Rabat, Morocco." href="#short-view-affiliation-10" ref="linksrc=author_aff">
10
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Chebbar+I&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-label="Imane Chebbar">Imane Chebbar</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Service d&#x27;Ophtalmologie B, Hôpital des Spécialités, CHU Rabat, Faculté de médecine et de Pharmacie, Mohammed V University of Rabat, 10100, Rabat, Morocco." href="#short-view-affiliation-10" ref="linksrc=author_aff">
10
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Postma+AV&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-label="Alex V Postma">Alex V Postma</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Amsterdam UMC, University of Amsterdam, Department of Anatomy, Embryology &amp; Physiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, The Netherlands." href="#short-view-affiliation-11" ref="linksrc=author_aff">
11
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Lougaris+V&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-label="Vassilios Lougaris">Vassilios Lougaris</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Pediatrics Clinic and Institute for Molecular Medicine &quot;A. Nocivelli&quot;, Department of Clinical and Experimental Sciences, University of Brescia and ASST-Spedali Civili of Brescia, 25123, Brescia, Italy." href="#short-view-affiliation-12" ref="linksrc=author_aff">
12
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Plebani+A&amp;cauthor_id=30862798"
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data-ga-label="Alessandro Plebani">Alessandro Plebani</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Pediatrics Clinic and Institute for Molecular Medicine &quot;A. Nocivelli&quot;, Department of Clinical and Experimental Sciences, University of Brescia and ASST-Spedali Civili of Brescia, 25123, Brescia, Italy." href="#short-view-affiliation-12" ref="linksrc=author_aff">
12
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Altmueller+J&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-label="Janine Altmueller">Janine Altmueller</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Cologne Center for Genomics University of Cologne, 50931, Cologne, Germany." href="#short-view-affiliation-13" ref="linksrc=author_aff">
13
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, 50931, Germany." href="#short-view-affiliation-14" ref="linksrc=author_aff">
14
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Institute of Human Genetics, University of Cologne, 50931, Cologne, Germany." href="#short-view-affiliation-15" ref="linksrc=author_aff">
15
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Kyrieleis+H&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-label="Henriette Kyrieleis">Henriette Kyrieleis</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pediatrics, Bethanien Hospital, Cologne, 42699, Germany." href="#short-view-affiliation-16" ref="linksrc=author_aff">
16
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Meiner+V&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-label="Vardiella Meiner">Vardiella Meiner</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel." href="#short-view-affiliation-17" ref="linksrc=author_aff">
17
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=McNeill+H&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-label="Helen McNeill">Helen McNeill</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Developmental Biology, Washington University School of Medicine, St. Louis, 63110, MO, USA." href="#short-view-affiliation-18" ref="linksrc=author_aff">
18
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Bharti+K&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-label="Kapil Bharti">Kapil Bharti</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Unit on Ocular &amp; Stem Cell Translational Research, National Eye Institute, NIH, Bethesda, MD, 20892, USA." href="#short-view-affiliation-7" ref="linksrc=author_aff">
7
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Lyonnet+S&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
data-ga-category="search"
data-ga-action="author_link"
data-ga-label="Stanislas Lyonnet">Stanislas Lyonnet</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Laboratory of embryology and genetics of human malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, 75015, France." href="#short-view-affiliation-19" ref="linksrc=author_aff">
19
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Wollnik+B&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
data-ga-category="search"
data-ga-action="author_link"
data-ga-label="Bernd Wollnik">Bernd Wollnik</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Institute of Human Genetics, University Medical Center Goettingen, 37073, Goettingen, Germany." href="#short-view-affiliation-5" ref="linksrc=author_aff">
5
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Henrion-Caude+A&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-action="author_link"
data-ga-label="Alexandra Henrion-Caude">Alexandra Henrion-Caude</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="INSERM UMR-781, Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (APHP), Paris, 75015, France." href="#short-view-affiliation-20" ref="linksrc=author_aff">
20
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Berraho+A&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
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data-ga-action="author_link"
data-ga-label="Amina Berraho">Amina Berraho</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Service d&#x27;Ophtalmologie B, Hôpital des Spécialités, CHU Rabat, Faculté de médecine et de Pharmacie, Mohammed V University of Rabat, 10100, Rabat, Morocco." href="#short-view-affiliation-10" ref="linksrc=author_aff">
10
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Hildebrandt+F&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
data-ga-category="search"
data-ga-action="author_link"
data-ga-label="Friedhelm Hildebrandt">Friedhelm Hildebrandt</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pediatrics, Boston Children&#x27;s Hospital, Harvard Medical School, Boston, MA, 02115, USA." href="#short-view-affiliation-4" ref="linksrc=author_aff">
4
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Bezzina+CR&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
data-ga-category="search"
data-ga-action="author_link"
data-ga-label="Connie R Bezzina">Connie R Bezzina</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, 1105AZ, The Netherlands. c.r.bezzina@amc.uva.nl." href="#short-view-affiliation-21" ref="linksrc=author_aff">
21
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Brooks+BP&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
data-ga-category="search"
data-ga-action="author_link"
data-ga-label="Brian P Brooks">Brian P Brooks</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, 20892, USA. brooksb@nei.nih.gov." href="#short-view-affiliation-22" ref="linksrc=author_aff">
22
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Sefiani+A&amp;cauthor_id=30862798"
ref="linksrc=author_name_link"
data-ga-category="search"
data-ga-action="author_link"
data-ga-label="Abdelaziz Sefiani">Abdelaziz Sefiani</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Centre de Recherche en Génomique des Pathologies Humaines (GENOPATH), Faculté de Médecine et de Pharmacie, Mohammed V University of Rabat, 10100, Rabat, Morocco. sefianigen@hotmail.com." href="#short-view-affiliation-23" ref="linksrc=author_aff">
23
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Département de génétique médicale, Institut National d&#x27;Hygiène, BP 769 Agdal, 10090, Rabat, Morocco. sefianigen@hotmail.com." href="#short-view-affiliation-24" ref="linksrc=author_aff">
24
</a></sup></span>
</div>
</div>
<div class="affiliations">
<h3 class="title">
Affiliations
</h3>
<ul class="item-list">
<li data-affiliation-id="short-view-affiliation-1"
id="short-view-affiliation-1"
><sup class="key">1</sup> Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, 1105AZ, The Netherlands.</li>
<li data-affiliation-id="short-view-affiliation-2"
id="short-view-affiliation-2"
><sup class="key">2</sup> Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, 20892, USA.</li>
<li data-affiliation-id="short-view-affiliation-3"
id="short-view-affiliation-3"
><sup class="key">3</sup> Centre de Recherche en Génomique des Pathologies Humaines (GENOPATH), Faculté de Médecine et de Pharmacie, Mohammed V University of Rabat, 10100, Rabat, Morocco.</li>
<li data-affiliation-id="short-view-affiliation-4"
id="short-view-affiliation-4"
><sup class="key">4</sup> Department of Pediatrics, Boston Children&#x27;s Hospital, Harvard Medical School, Boston, MA, 02115, USA.</li>
<li data-affiliation-id="short-view-affiliation-5"
id="short-view-affiliation-5"
><sup class="key">5</sup> Institute of Human Genetics, University Medical Center Goettingen, 37073, Goettingen, Germany.</li>
<li data-affiliation-id="short-view-affiliation-6"
id="short-view-affiliation-6"
><sup class="key">6</sup> Boston Children&#x27;s Hospital and Harvard Medical School, Boston, MA, 02215, USA.</li>
<li data-affiliation-id="short-view-affiliation-7"
id="short-view-affiliation-7"
><sup class="key">7</sup> Unit on Ocular &amp; Stem Cell Translational Research, National Eye Institute, NIH, Bethesda, MD, 20892, USA.</li>
<li data-affiliation-id="short-view-affiliation-8"
id="short-view-affiliation-8"
><sup class="key">8</sup> Section of Histopathology, National Eye Institute, NIH, Bethesda, MD, 20892, USA.</li>
<li data-affiliation-id="short-view-affiliation-9"
id="short-view-affiliation-9"
><sup class="key">9</sup> Département de génétique médicale, Institut National d&#x27;Hygiène, BP 769 Agdal, 10090, Rabat, Morocco.</li>
<li data-affiliation-id="short-view-affiliation-10"
id="short-view-affiliation-10"
><sup class="key">10</sup> Service d&#x27;Ophtalmologie B, Hôpital des Spécialités, CHU Rabat, Faculté de médecine et de Pharmacie, Mohammed V University of Rabat, 10100, Rabat, Morocco.</li>
<li data-affiliation-id="short-view-affiliation-11"
id="short-view-affiliation-11"
><sup class="key">11</sup> Amsterdam UMC, University of Amsterdam, Department of Anatomy, Embryology &amp; Physiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, The Netherlands.</li>
<li data-affiliation-id="short-view-affiliation-12"
id="short-view-affiliation-12"
><sup class="key">12</sup> Pediatrics Clinic and Institute for Molecular Medicine &quot;A. Nocivelli&quot;, Department of Clinical and Experimental Sciences, University of Brescia and ASST-Spedali Civili of Brescia, 25123, Brescia, Italy.</li>
<li data-affiliation-id="short-view-affiliation-13"
id="short-view-affiliation-13"
><sup class="key">13</sup> Cologne Center for Genomics University of Cologne, 50931, Cologne, Germany.</li>
<li data-affiliation-id="short-view-affiliation-14"
id="short-view-affiliation-14"
><sup class="key">14</sup> Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, 50931, Germany.</li>
<li data-affiliation-id="short-view-affiliation-15"
id="short-view-affiliation-15"
><sup class="key">15</sup> Institute of Human Genetics, University of Cologne, 50931, Cologne, Germany.</li>
<li data-affiliation-id="short-view-affiliation-16"
id="short-view-affiliation-16"
><sup class="key">16</sup> Department of Pediatrics, Bethanien Hospital, Cologne, 42699, Germany.</li>
<li data-affiliation-id="short-view-affiliation-17"
id="short-view-affiliation-17"
><sup class="key">17</sup> Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.</li>
<li data-affiliation-id="short-view-affiliation-18"
id="short-view-affiliation-18"
><sup class="key">18</sup> Department of Developmental Biology, Washington University School of Medicine, St. Louis, 63110, MO, USA.</li>
<li data-affiliation-id="short-view-affiliation-19"
id="short-view-affiliation-19"
><sup class="key">19</sup> Laboratory of embryology and genetics of human malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, 75015, France.</li>
<li data-affiliation-id="short-view-affiliation-20"
id="short-view-affiliation-20"
><sup class="key">20</sup> INSERM UMR-781, Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (APHP), Paris, 75015, France.</li>
<li data-affiliation-id="short-view-affiliation-21"
id="short-view-affiliation-21"
><sup class="key">21</sup> Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, 1105AZ, The Netherlands. c.r.bezzina@amc.uva.nl.</li>
<li data-affiliation-id="short-view-affiliation-22"
id="short-view-affiliation-22"
><sup class="key">22</sup> Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, 20892, USA. brooksb@nei.nih.gov.</li>
<li data-affiliation-id="short-view-affiliation-23"
id="short-view-affiliation-23"
><sup class="key">23</sup> Centre de Recherche en Génomique des Pathologies Humaines (GENOPATH), Faculté de Médecine et de Pharmacie, Mohammed V University of Rabat, 10100, Rabat, Morocco. sefianigen@hotmail.com.</li>
<li data-affiliation-id="short-view-affiliation-24"
id="short-view-affiliation-24"
><sup class="key">24</sup> Département de génétique médicale, Institut National d&#x27;Hygiène, BP 769 Agdal, 10090, Rabat, Morocco. sefianigen@hotmail.com.</li>
</ul>
</div>
</div>
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A failure in optic fissure fusion during development can lead to blinding malformations of the eye. Here, we report a syndrome characterized by facial dysmorphism, colobomatous microphthalmia, ptosis and syndactyly with or without nephropathy, associated with homozygous frameshift mutations in FAT1. We show that Fat1 knockout mice and zebrafish embryos homozygous for truncating fat1a mutations exhibit completely penetrant coloboma, recapitulating the most consistent developmental defect observed in affected individuals. In human retinal pigment epithelium (RPE) cells, the primary site for the fusion of optic fissure margins, FAT1 is localized at earliest cell-cell junctions, consistent with a role in facilitating optic fissure fusion during vertebrate eye development. Our findings establish FAT1 as a gene with pleiotropic effects in human, in that frameshift mutations cause a severe multi-system disorder whereas recessive missense mutations had been previously associated with isolated glomerulotubular nephropathy.
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<div class="figure-caption-contents"><p> Recessive frameshift mutations in <i> FAT1… </i> </p></div>
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<div class="figure-caption-contents"><p> Recessive frameshift mutations in <i> FAT1 </i> cause a new clinical syndrome. Pedigree of family… </p></div>
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Fig. 1
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<div class="figure-caption-contents">Recessive frameshift mutations in <i>FAT1</i> cause a new clinical syndrome. Pedigree of family 15 (<b>a</b>). A schematic of human <i>FAT1</i> start/stop codon, exons, location of mutations previous published and identified in this study (top panel). The FAT1 protein is 4588 amino acids long and contains 34 cadherin repeats (CA), followed by five epidermal growth factor (EGF)-like repeat domains (E), a laminin G domain (LamG), a transmembrane domain (green), and an intracellular domain (bottom panel). Family 1 and 2 were found to carry the same homozygous frameshift variant c.2207dupT (p.I737NfsX7) in <i>FAT1 (</i>NM_005245). In Families 35 we identified, respectively, the following homozygous frameshift <i>FAT1</i> variants: c.2600_2601delCA (p.T867IfsX4), c.9729del p.(V3245LfsX25), and c.3093_3096del (p.P1032CgsX11). H homozygous, h heterozygous (<b>b</b>). Ophthalmic features observed in patients included ptosis; bilateral in patients F1-IV-1, F1-IV-3, F1-IV-5, F2-III-3, F2-IV-3, F3-IV-1 and unilateral in F2-IV-1, F4-II-3 (<b>c</b>), microphthalmia (<b>d</b>), iris coloboma (<b>e</b>), large chorioretinal coloboma containing the papilla/optic nerve with two other smaller circumscribed chorioretinal colobomas localized above the papilla (<b>f</b>), and retinal coloboma (<b>g</b>). Skeletal abnormalities included syndactyly in the majority of patients and bone fusion of phalanges 34 on the right foot and hypotrophy of phalanx 2 of the left foot in patient F3-II-2 (<b>h</b>). X-ray of the feet demonstrating cutaneous syndactyly in patient F2-IV-1 (<b>i</b>)</div>
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<div class="figure-caption-contents"><i> FAT1 </i> <sup> -/- </sup> mouse exhibit microphthalmia…</div>
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<p> Fig. 2 </p>
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<div class="figure-caption-contents"><i> FAT1 </i> <sup> -/- </sup> mouse exhibit microphthalmia and completely penetrant coloboma. <i> FAT1 </i> mRNA expression pattern…</div>
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Fig. 2
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<div class="figure-caption-contents"><i>FAT1</i><sup>-/-</sup> mouse exhibit microphthalmia and completely penetrant coloboma. <i>FAT1</i> mRNA expression pattern in sagittal (<b>a</b><b>c</b>) and coronal (<b>d</b><b>f</b>) mouse optic cup sections at E10.5 (<b>a</b>, <b>d</b>), E11.5 (<b>b</b>, <b>e</b>), and E12.5 (<b>c</b>, <b>f</b>). Compared to wild-type (WT) embryos (<b>g</b><b>i</b>, E14.5) <i>FAT1</i><sup>/</sup> mouse exhibited microphthalmia (<b>j</b>, <b>m</b>). Fused optic fissure margins of WT mouse embryos (E14.5, <b>h</b>, <b>i</b>; sagittal section) and unfused margins were seen in <i>Fat1</i><sup>/</sup> mice (<b>n</b>, <b>o</b>) and/or persistence of POM—including early hyaloid vessel precursors (<b>k</b>, <b>l</b>, arrow) interposing between the closing edges of the fissure (E14.5). D dorsal, V ventral, T temporal, N nasal</div>
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<div class="figure-caption-contents"><p> FAT1 knockdown disrupts F-ACTIN and… </p></div>
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<div class="figure-caption-contents"><p> FAT1 knockdown disrupts F-ACTIN and ZO-1 localization in RPE. ShRNA-mediated knockdown of FAT1… </p></div>
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Fig. 3
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<div class="figure-caption-contents">FAT1 knockdown disrupts F-ACTIN and ZO-1 localization in RPE. ShRNA-mediated knockdown of FAT1 in RPE cells was confirmed using Western blotting (<b>a</b>, <i>N</i>=3). Disorganization of F-ACTIN fibers (<b>b</b>) and loss of ZO-1 staining pattern (<b>c</b>) was observed in RPE cells upon knockdown of FAT1. Trans-epithelial electrical resistance was measured at week one and two post-FAT1 knockdown to determine junctional integrity (<b>d</b>, <i>N</i>=6). Scale bar is 20µm. Error bars represent standard error of mean, and statistical significance is at <i>P</i>&lt;0.05 (two tailed <i>t</i>-test) denoted by “*”. Raw data is provided in supplementary section</div>
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<div class="figure-caption-contents"><p> FAT1 knockdown results in a… </p></div>
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<div class="figure-caption-contents"><p> FAT1 knockdown results in a failure to organize RPE cells into a monolayer.… </p></div>
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<div class="figure-caption-contents">FAT1 knockdown results in a failure to organize RPE cells into a monolayer. Transmission electron miscroscopy (TEM) of RPE cells cultured on trans-wells for 2 weeks following treatment with scrambled (<b>a</b>, <b>c</b>) and FAT1 shRNA (<b>b</b>, <b>d</b>). A transverse section depicting RPE cells (*, scale bar is 2µm) sitting on top of trans-well membrane (<b>a</b>, arrow). A higher magnification showing epithelial tight junction (<b>c</b>, <b>d</b>, arrow, scale bar is 500nm) between two neighboring cells</div>
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<div class="figure-caption-contents"><p> Zebrafish embryos with homozygous alleles of truncated <i> fat1a </i> display coloboma. CRISPR/Cas9-mediated introduction of… </p></div>
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<div class="figure-caption-contents">Zebrafish embryos with homozygous alleles of truncated <i>fat1a</i> display coloboma. CRISPR/Cas9-mediated introduction of frame-shift mutations in FAT1 C-terminal resulted in optic fissure closure defects (<b>a</b> and <b>e</b>, scale bar is 0.1mm). A higher magnification of eye depicting fused margins in WT and unfused margins in homozygous mutant (*, <b>b</b> and <b>f</b>, scale bar is 0.05mm). Sagittal sections of zebrafish embryos (2430 hpf) followed by toludene blue staining showing organization of the optic cup (<b>c</b> and <b>g</b>, scale bar is 50µm). Higher magnification of the optic cup shows morphology of optic fissure margins in WT and homozygous mutant (<b>d</b>, <b>h</b>, scale bar is 20µm)</div>
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