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Homozygous splice mutation in CWF19L1 in a Turkish family with recessive ataxia syndrome

Identifieur interne : 000A46 ( Main/Exploration ); précédent : 000A45; suivant : 000A47

Homozygous splice mutation in CWF19L1 in a Turkish family with recessive ataxia syndrome

Auteurs : Randi Burns ; Karen Majczenko ; Jishu Xu ; Weiping Peng ; Zuhal Yapici ; James J. Dowling ; Jun Z. Li ; Margit Burmeister

Source :

Neurology [ 0028-3878 ] ; 2014.

RBID : PMC:4276403

Abstract

Objective:

To elucidate the genetic cause of a rare recessive ataxia presented by 2 siblings from a consanguineous Turkish family with a nonprogressive, congenital ataxia with mental retardation of unknown etiology.

Methods:

Whole-exome sequencing was combined with homozygosity mapping, linkage, and expression analysis to identify candidate genes, confirmed by Sanger sequencing. Reverse transcription–PCR and immunoblotting were used to determine the functional consequences of the gene variant. A zebrafish model was developed using morpholino-mediated knockdown.

Results:

We identified a homozygous mutation at the invariant +1 position (c.964+1G>A) in intron 9 of the CWF19L1 (complexed with cdc5 protein 19-like 1) gene. This mutation is absent in >6,500 European and African American individuals and 200 Turkish control DNAs. The mutation causes exon skipping, reduction in messenger RNA levels, and protein loss in cell lines of affected individuals. Morpholino-mediated knockdown in a zebrafish model demonstrates that loss of the evolutionarily highly conserved CWF19L1, whose normal biological function is unknown, alters cerebellar morphology and causes movement abnormalities.

Conclusions:

Our results suggest that CWF19L1 mutations may be a novel cause of recessive ataxia with developmental delay. Our research may help with diagnosis, especially in Turkey, identify causes of other ataxias, and may lead to novel therapies.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276403

DOI: 10.1212/WNL.0000000000001053
PubMed: 25361784
PubMed Central: 4276403

Affiliations:

Le document en format XML

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<front><div type="abstract" xml:lang="en"><sec><title>Objective:</title>
<p>To elucidate the genetic cause of a rare recessive ataxia presented by 2 siblings from a consanguineous Turkish family with a nonprogressive, congenital ataxia with mental retardation of unknown etiology.</p>
</sec>
<sec><title>Methods:</title>
<p>Whole-exome sequencing was combined with homozygosity mapping, linkage, and expression analysis to identify candidate genes, confirmed by Sanger sequencing. Reverse transcription–PCR and immunoblotting were used to determine the functional consequences of the gene variant. A zebrafish model was developed using morpholino-mediated knockdown.</p>
</sec>
<sec><title>Results:</title>
<p>We identified a homozygous mutation at the invariant +1 position (c.964+1G>A) in intron 9 of the <italic>CWF19L1</italic>
 (complexed with cdc5 protein 19-like 1) gene. This mutation is absent in >6,500 European and African American individuals and 200 Turkish control DNAs. The mutation causes exon skipping, reduction in messenger RNA levels, and protein loss in cell lines of affected individuals. Morpholino-mediated knockdown in a zebrafish model demonstrates that loss of the evolutionarily highly conserved <italic>CWF19L1</italic>
, whose normal biological function is unknown, alters cerebellar morphology and causes movement abnormalities.</p>
</sec>
<sec><title>Conclusions:</title>
<p>Our results suggest that <italic>CWF19L1</italic>
 mutations may be a novel cause of recessive ataxia with developmental delay. Our research may help with diagnosis, especially in Turkey, identify causes of other ataxias, and may lead to novel therapies.</p>
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<name sortKey="Li, Jun Z" sort="Li, Jun Z" uniqKey="Li J" first="Jun Z." last="Li">Jun Z. Li</name>
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<name sortKey="Peng, Weiping" sort="Peng, Weiping" uniqKey="Peng W" first="Weiping" last="Peng">Weiping Peng</name>
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Homozygous splice mutation in CWF19L1 in a Turkish family with recessive ataxia syndrome

Homozygous splice mutation in CWF19L1 in a Turkish family with recessive ataxia syndrome

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Abstract

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