AustralieFrV1, Main, Exploration, bibRecord, 006C70

Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database

Identifieur interne : 006C70 ( Main/Exploration ); précédent : 006C69; suivant : 006C71

Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database

Auteurs : Ofir T. Betsalel [Pays-Bas] ; Efraim H. Rosenberg [Pays-Bas] ; Ligia S. Almeida [Pays-Bas, Portugal] ; Tjitske Kleefstra [Pays-Bas] ; Charles E. Schwartz [États-Unis] ; Vassili Valayannopoulos [France] ; Omar Abdul-Rahman [États-Unis] ; Nicola Poplawski [Australie] ; Laura Vilarinho [Portugal] ; Philipp Wolf [Allemagne] ; Johan T. Den Dunnen [Pays-Bas] ; Cornelis Jakobs [Pays-Bas] ; Gajja S. Salomons [Pays-Bas]

Source :

European journal of human genetics [ 1018-4813 ] ; 2011.

RBID : Pascal:11-0109292

Descripteurs français

Pascal (Inist)
- Syndrome complexe, Caractérisation, Variant, Utilisation, Epissage, Epissure, Site, Implémentation, Base de données, Génétique.
Wicri :
- topic : Base de données, Génétique.

English descriptors

KwdEn :
- Characterization, Complex syndrome, Database, Genetics, Implementation, Site, Splice, Splicing, Use, Variant.

Abstract

The X-linked creatine transporter defect is caused by mutations in the SLC6A8 gene. Until now, 66 synonymous and intronic variants in SLC6A8 were detected in our laboratory. To gain more insight in the effect of the detected variants, we applied five free web-based splice-site analysis tools to 25 published variants that were stratified as (non-)disease causing. All were correctly predicted to have no effect (n=18) or to cause erroneous splicing (n=7), with the exception of a pathogenic de novo 24 bp intronic deletion. Second, 41 unclassified variants, including 28 novel, were subjected to analysis by these tools. At least four splice-site analysis tools predicted that three of the variants would affect splicing as the mutations disrupted the canonical splice site. Urinary creatine/creatinine and brain MRS confirmed creatine transporter deficiency in five patients (four families), including one female. Another variant was predicted to moderately affect splicing by all five tools. However, transient transfection of a minigene containing the variant in a partial SLC6A8 segment showed no splicing errors, and thus was finally classified as non-disease causing. This study shows that splice tools are useful for the characterization of the majority of variants, but also illustrates that the actual effect can be misclassified in rare occasions. Therefore, further laboratory studies should be considered before final conclusions on the disease-causing nature are drawn. To provide an accessible database, the 109 currently known SLC6A8 variants, including 35 novel ones, are included in a newly developed LOVD DNA variation database.

Affiliations:

Allemagne, Australie, France, Pays-Bas, Portugal, États-Unis
Gueldre, Hollande-Méridionale, Hollande-Septentrionale, Île-de-France
Amsterdam, Leyde, Nimègue, Paris

Links toward previous steps (curation, corpus...)

to stream PascalFrancis, to step Corpus: 001F98
to stream PascalFrancis, to step Curation: 003F36
to stream PascalFrancis, to step Checkpoint: 001C78
to stream Main, to step Merge: 007129
to stream Main, to step Curation: 006C70

Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Characterization</term>
<term>Complex syndrome</term>
<term>Database</term>
<term>Genetics</term>
<term>Implementation</term>
<term>Site</term>
<term>Splice</term>
<term>Splicing</term>
<term>Use</term>
<term>Variant</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Syndrome complexe</term>
<term>Caractérisation</term>
<term>Variant</term>
<term>Utilisation</term>
<term>Epissage</term>
<term>Epissure</term>
<term>Site</term>
<term>Implémentation</term>
<term>Base de données</term>
<term>Génétique</term>
</keywords>
<keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Base de données</term>
<term>Génétique</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">The X-linked creatine transporter defect is caused by mutations in the SLC6A8 gene. Until now, 66 synonymous and intronic variants in SLC6A8 were detected in our laboratory. To gain more insight in the effect of the detected variants, we applied five free web-based splice-site analysis tools to 25 published variants that were stratified as (non-)disease causing. All were correctly predicted to have no effect (n=18) or to cause erroneous splicing (n=7), with the exception of a pathogenic de novo 24 bp intronic deletion. Second, 41 unclassified variants, including 28 novel, were subjected to analysis by these tools. At least four splice-site analysis tools predicted that three of the variants would affect splicing as the mutations disrupted the canonical splice site. Urinary creatine/creatinine and brain MRS confirmed creatine transporter deficiency in five patients (four families), including one female. Another variant was predicted to moderately affect splicing by all five tools. However, transient transfection of a minigene containing the variant in a partial SLC6A8 segment showed no splicing errors, and thus was finally classified as non-disease causing. This study shows that splice tools are useful for the characterization of the majority of variants, but also illustrates that the actual effect can be misclassified in rare occasions. Therefore, further laboratory studies should be considered before final conclusions on the disease-causing nature are drawn. To provide an accessible database, the 109 currently known SLC6A8 variants, including 35 novel ones, are included in a newly developed LOVD DNA variation database.</div>
</front>
</TEI>
<affiliations><list><country><li>Allemagne</li>
<li>Australie</li>
<li>France</li>
<li>Pays-Bas</li>
<li>Portugal</li>
<li>États-Unis</li>
</country>
<region><li>Gueldre</li>
<li>Hollande-Méridionale</li>
<li>Hollande-Septentrionale</li>
<li>Île-de-France</li>
</region>
<settlement><li>Amsterdam</li>
<li>Leyde</li>
<li>Nimègue</li>
<li>Paris</li>
</settlement>
</list>
<tree><country name="Pays-Bas"><region name="Hollande-Septentrionale"><name sortKey="Betsalel, Ofir T" sort="Betsalel, Ofir T" uniqKey="Betsalel O" first="Ofir T." last="Betsalel">Ofir T. Betsalel</name>
</region>
<name sortKey="Almeida, Ligia S" sort="Almeida, Ligia S" uniqKey="Almeida L" first="Ligia S." last="Almeida">Ligia S. Almeida</name>
<name sortKey="Den Dunnen, Johan T" sort="Den Dunnen, Johan T" uniqKey="Den Dunnen J" first="Johan T." last="Den Dunnen">Johan T. Den Dunnen</name>
<name sortKey="Jakobs, Cornelis" sort="Jakobs, Cornelis" uniqKey="Jakobs C" first="Cornelis" last="Jakobs">Cornelis Jakobs</name>
<name sortKey="Kleefstra, Tjitske" sort="Kleefstra, Tjitske" uniqKey="Kleefstra T" first="Tjitske" last="Kleefstra">Tjitske Kleefstra</name>
<name sortKey="Rosenberg, Efraim H" sort="Rosenberg, Efraim H" uniqKey="Rosenberg E" first="Efraim H." last="Rosenberg">Efraim H. Rosenberg</name>
<name sortKey="Rosenberg, Efraim H" sort="Rosenberg, Efraim H" uniqKey="Rosenberg E" first="Efraim H." last="Rosenberg">Efraim H. Rosenberg</name>
<name sortKey="Salomons, Gajja S" sort="Salomons, Gajja S" uniqKey="Salomons G" first="Gajja S." last="Salomons">Gajja S. Salomons</name>
</country>
<country name="Portugal"><noRegion><name sortKey="Almeida, Ligia S" sort="Almeida, Ligia S" uniqKey="Almeida L" first="Ligia S." last="Almeida">Ligia S. Almeida</name>
</noRegion>
<name sortKey="Vilarinho, Laura" sort="Vilarinho, Laura" uniqKey="Vilarinho L" first="Laura" last="Vilarinho">Laura Vilarinho</name>
</country>
<country name="États-Unis"><noRegion><name sortKey="Schwartz, Charles E" sort="Schwartz, Charles E" uniqKey="Schwartz C" first="Charles E." last="Schwartz">Charles E. Schwartz</name>
</noRegion>
<name sortKey="Abdul Rahman, Omar" sort="Abdul Rahman, Omar" uniqKey="Abdul Rahman O" first="Omar" last="Abdul-Rahman">Omar Abdul-Rahman</name>
</country>
<country name="France"><region name="Île-de-France"><name sortKey="Valayannopoulos, Vassili" sort="Valayannopoulos, Vassili" uniqKey="Valayannopoulos V" first="Vassili" last="Valayannopoulos">Vassili Valayannopoulos</name>
</region>
</country>
<country name="Australie"><noRegion><name sortKey="Poplawski, Nicola" sort="Poplawski, Nicola" uniqKey="Poplawski N" first="Nicola" last="Poplawski">Nicola Poplawski</name>
</noRegion>
</country>
<country name="Allemagne"><noRegion><name sortKey="Wolf, Philipp" sort="Wolf, Philipp" uniqKey="Wolf P" first="Philipp" last="Wolf">Philipp Wolf</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database

Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database

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