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<meta name="description" content="We suggest SPL deficiency as a cause of a distinct form of Charcot-Marie-Tooth disease in humans, thus extending the currently recognized clinical and genetic spectrum of inherited peripheral neuropathies. Our data emphasize the importance of sphingolipid metabolism for neuronal function."><meta name="keywords" content="pmid:28077491, PMC5304460, doi:10.1212/WNL.0000000000003595, Case Reports, Derek Atkinson, Jelena Nikodinovic Glumac, Albena Jordanova, Adult, Aldehyde-Lyases / deficiency*, Aldehyde-Lyases / genetics*, Aldehyde-Lyases / metabolism*, Animals, Animals, Genetically Modified, Cells, Cultured, Charcot-Marie-Tooth Disease / genetics*, Charcot-Marie-Tooth Disease / physiopathology, Codon, Nonsense*, Cohort Studies, Drosophila Proteins / genetics, Drosophila Proteins / metabolism*, Drosophila melanogaster, Female, Humans, Lymphocytes / metabolism, Lymphocytes / pathology, Lysophospholipids / blood, Male, Mutation, Missense*, Neurons / metabolism, Neurons / pathology, Siblings, Sphingosine / analogs &amp; derivatives, Sphingosine / blood, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta property="og:title" content="Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/28077491/"><meta property="og:description" content="We suggest SPL deficiency as a cause of a distinct form of Charcot-Marie-Tooth disease in humans, thus extending the currently recognized clinical and genetic spectrum of inherited peripheral neuropathies. Our data emphasize the importance of sphingolipid metabolism for neuronal function."><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/28077491/"><meta name="twitter:description" content="We suggest SPL deficiency as a cause of a distinct form of Charcot-Marie-Tooth disease in humans, thus extending the currently recognized clinical and genetic spectrum of inherited peripheral neuropathies. Our data emphasize the importance of sphingolipid metabolism for neuronal function."><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">
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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="vZclKM6HqSRpgRPIbmyDmQA8C1mAifqBMMWqnCz30tETaiVyOFbFQY6Ma54MbQYV">
<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="vZclKM6HqSRpgRPIbmyDmQA8C1mAifqBMMWqnCz30tETaiVyOFbFQY6Ma54MbQYV">
<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="vZclKM6HqSRpgRPIbmyDmQA8C1mAifqBMMWqnCz30tETaiVyOFbFQY6Ma54MbQYV">
<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="vZclKM6HqSRpgRPIbmyDmQA8C1mAifqBMMWqnCz30tETaiVyOFbFQY6Ma54MbQYV">
<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="vZclKM6HqSRpgRPIbmyDmQA8C1mAifqBMMWqnCz30tETaiVyOFbFQY6Ma54MbQYV">
<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="28077491">
<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.neurology.org/doi/10.1212/WNL.0000000000003595?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub 0pubmed"
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ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=4487&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=28077491&amp;db=pubmed&amp;nlmid=0401060"
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Atypon
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pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/28077491/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=28077491&amp;db=pubmed&amp;nlmid=0401060"
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data-ga-category="full_text"
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Free PMC article
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</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="/28077491/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/28077491/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="28077491" 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%2F28077491%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="vZclKM6HqSRpgRPIbmyDmQA8C1mAifqBMMWqnCz30tETaiVyOFbFQY6Ma54MbQYV"><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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<h1 class="heading-title">
Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy
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><sup class="key">1</sup> From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.</li>
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><sup class="key">2</sup> From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland. albena.jordanova@molgen.vib-ua.be vedrana.milic.npk@gmail.com.</li>
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<div class="publication-type" >Case Reports</div>
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Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy
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<span class="authors-list-item "><span class="full-name">Derek Atkinson</span><span class="citation-separator">&nbsp;et al.</span></span>
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<span class="authors-list-item "><a class="full-name"
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data-ga-label="Derek Atkinson">Derek Atkinson</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland." 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"
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data-ga-label="Jelena Nikodinovic Glumac">Jelena Nikodinovic Glumac</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland." 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"
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data-ga-label="Bob Asselbergh">Bob Asselbergh</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland." 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"
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data-ga-label="Biljana Ermanoska">Biljana Ermanoska</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="David Blocquel">David Blocquel</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Regula Steiner">Regula Steiner</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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data-ga-label="Alejandro Estrada-Cuzcano">Alejandro Estrada-Cuzcano</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Tinne Ooms">Tinne Ooms</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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data-ga-label="Els De Vriendt">Els De Vriendt</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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data-ga-label="Xiang-Lei Yang">Xiang-Lei Yang</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland." href="#short-view-affiliation-1" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Vedrana Milic Rasic">Vedrana Milic Rasic</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland. albena.jordanova@molgen.vib-ua.be vedrana.milic.npk@gmail.com." href="#short-view-affiliation-2" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Albena Jordanova">Albena Jordanova</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland. albena.jordanova@molgen.vib-ua.be vedrana.milic.npk@gmail.com." href="#short-view-affiliation-2" ref="linksrc=author_aff">
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><sup class="key">1</sup> From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.</li>
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><sup class="key">2</sup> From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland. albena.jordanova@molgen.vib-ua.be vedrana.milic.npk@gmail.com.</li>
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Objective:
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To identify the unknown genetic cause in a nuclear family with an axonal form of peripheral neuropathy and atypical disease course.
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Methods:
</strong>
Detailed neurologic, electrophysiologic, and neuropathologic examinations of the patients were performed. Whole exome sequencing of both affected individuals was done. The effect of the identified sequence variations was investigated at cDNA and protein level in patient-derived lymphoblasts. The plasma sphingoid base profile was analyzed. Functional consequences of neuron-specific downregulation of the gene were studied in Drosophila.
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Results:
</strong>
Both patients present an atypical form of axonal peripheral neuropathy, characterized by acute or subacute onset and episodes of recurrent mononeuropathy. We identified compound heterozygous mutations cosegregating with disease and absent in controls in the SGPL1 gene, encoding sphingosine 1-phosphate lyase (SPL). The p.Ser361* mutation triggers nonsense-mediated mRNA decay. The missense p.Ile184Thr mutation causes partial protein degradation. The plasma levels of sphingosine 1-phosphate and sphingosine/sphinganine ratio were increased in the patients. Neuron-specific downregulation of the Drosophila orthologue impaired the morphology of the neuromuscular junction and caused progressive degeneration of the chemosensory neurons innervating the wing margin bristles.
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Conclusions:
</strong>
We suggest SPL deficiency as a cause of a distinct form of Charcot-Marie-Tooth disease in humans, thus extending the currently recognized clinical and genetic spectrum of inherited peripheral neuropathies. Our data emphasize the importance of sphingolipid metabolism for neuronal function.
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<p> Figure 1. Pedigree and clinical features of… </p>
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<p> Figure 1. Pedigree and clinical features of the studied autosomal recessive Charcot-Marie-Tooth 2 family </p>
</strong>
<div class="figure-caption-contents"><p> (A)… </p></div>
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<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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Figure 1. Pedigree and clinical features of the studied autosomal recessive Charcot-Marie-Tooth 2 family
</strong>
<div class="figure-caption-contents">(A) Family tree. Square symbols represent males and circles females. Black symbols indicate affected individuals. (B) Serial images of the patients. Patient II-1 at age 32 presents with unilateral mild hypotrophy and weakness of the muscles in the first interosseal space, bilateral atrophy, and severe weakness (Medical Research Council scale 02) of all distal leg muscles. Patient II-2 at age 28 has normal appearance of the distal muscles of the hands, unilateral severe weakness of hallux extensor, and normal standing on tiptoe.</div>
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<p> Figure 2. Sphingosine 1-phosphate (S1P) lyase (SPL):… </p>
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<p> Figure 2. Sphingosine 1-phosphate (S1P) lyase (SPL): Transcript, protein, and metabolite analysis </p>
</strong>
<div class="figure-caption-contents"><p> (A) Electropherograms around… </p></div>
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Figure 2. Sphingosine 1-phosphate (S1P) lyase (SPL): Transcript, protein, and metabolite analysis
</strong>
<div class="figure-caption-contents">(A) Electropherograms around the 2 mutations in <i>SGPL1</i> (c.551T&gt;C and c.1082C&gt;G) upon analyzing genomic DNA (gDNA) or complementary DNA (cDNA) isolated from peripheral mononuclear blood cells, before and after cycloheximide (CHX) treatment. (B) Crystal structure of the dimeric human sphingosine 1-phosphate lyase, adapted from pdb 4Q6R. The 2 subunits (A, B) of the dimeric protein are displayed in tan and blue ribbons, respectively. Top right: zoom in view shows the Ile184 residue that is surrounded by 7 other hydrophobic residues (i.e., Ala163, Phe167, Leu181, Ala402, Trp405 from subunit A; Leu130, Tyr133 from subunit B) to constitute a hydrophobic core. Bottom right: the p.Ile184Thr mutation substitutes the long aliphatic side chain of isoleucine with a small and polar hydroxyl group of threonine in the middle of the hydrophobic core. (C) Immunoblotting analysis of SPL in 20 μg of protein lysates of lymphoblast cultures from all family members and 7 healthy control individuals. β-actin is used as loading control. Chemiluminescence exposure time of 60 seconds. (D) Immunoblotting analysis of SPL in 30 μg of protein lysates of lymphoblasts of patient II-2 incubated with vehicle alone (DMSO), with the MG-132 proteasome inhibitor, or nontreated (NT). SPL accumulates in a time-dependent manner in cells from the patient, compared to the control. β-actin demonstrates equal loading. Chemiluminescence exposure time of 600 seconds. (E) S1P levels in plasma of patents, patients, and unrelated controls (n = 24). (F) Total sphingosine/sphinganine (SO/SA) ratio after hydrolysis in plasma of patients, parents, and unrelated controls (n = 3). (E, F) Error bars represent the SD. ***<i>p</i> &lt; 0.001; ns = nonsignificant (one-way analysis of variance with Bonferroni multiple comparison test against the control group).</div>
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<p> Figure 3. Analysis of neuron-specific <i> Sply </i> deficiency… </p>
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<p> Figure 3. Analysis of neuron-specific <i> Sply </i> deficiency in <i> Drosophila </i> </p>
</strong>
<div class="figure-caption-contents"><p> (A) Immunolabeling of presynaptic (anti-HRP antibody,… </p></div>
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<strong class="figure-label">
Figure 3. Analysis of neuron-specific <i>Sply</i> deficiency in <i>Drosophila</i>
</strong>
<div class="figure-caption-contents">(A) Immunolabeling of presynaptic (anti-HRP antibody, green) and postsynaptic (anti-DLG antibody, magenta) compartments of the neuromuscular junctions (NMJs) in third instar larvae, pan-neuronally (<i>nsyb-Gal4</i>) expressing RNAi constructs agains<i>t Sply</i> (Sply knockdown; <i>RNAi</i><sup><i>Sply[1]</i></sup>, <i>RNAi</i><sup><i>Sply[2]</i></sup>), neuronally relevant genes (<i>RNAi</i><sup><i>Smn</i></sup>, <i>RNAi</i><sup><i>Myc</i></sup>), genes not expressed in neurons (<i>RNAi controls; RNAi</i><sup><i>Cup</i></sup>, <i>RNAi</i><sup><i>S-Lap5[1]</i></sup>, <i>RNAi</i><sup><i>S-Lap[2]</i></sup>), or the driver alone (control genetic background; nsyb-Gal4/<i>+</i>). Scale bar, 20 μm. (BD) Quantitative analysis of the NMJ phenotypes. Maximum intensity projections of Z-stacks comprising the full NMJ were used. The number of boutons per NMJ (B) was counted using the Cell Counter plugin. ImageJ was used to count the number of individual branch segments (C) and calculate the total NMJ length (D). Error bars represent the SD of at least 13 NMJs per genotype. *<i>p</i> &lt; 0.05; ***<i>p</i> &lt; 0.001; ns = nonsignificant (one-way analysis of variance with Bonferroni multiple comparison test against the control genetic background). (E) Nerve tract along the wing L1 vein visualized by <i>mCherry</i>, where RNAi constructs are expressed using the <i>dpr-Gal4</i> driver. Representative images of wings are shown for day 1 and day 20+ old flies expressing the driver alone (<i>Dpr-Gal4/+</i>), neuronally relevant gene (<i>RNAi</i><sup><i>Smn</i></sup>), or Sply (<i>RNAi</i><sup><i>Sply[1]</i></sup>). Scale bar, 20 μm. (F) Quantification of the number of wings showing axonal fragmentation per genotype (n = 3060/genotype).</div>
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<div id="substances" class="substances keywords-section">
<h2 class="title">
Substances
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