• Je něco špatně v tomto záznamu ?

Characterization of a novel loss-of-function variant in TDP2 in two adult patients with spinocerebellar ataxia autosomal recessive 23 (SCAR23)

E. Errichiello, G. Zagnoli-Vieira, R. Rizzi, L. Garavelli, KW. Caldecott, O. Zuffardi

. 2020 ; 65 (12) : 1135-1141. [pub] 20200710

Jazyk angličtina Země Velká Británie

Typ dokumentu kazuistiky, časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc21019742

TDP2 encodes a 5'-tyrosyl DNA phosphodiesterase required for the efficient repair of double-strand breaks (DSBs) induced by the abortive activity of DNA topoisomerase II (TOP2). To date, only three homozygous variants in TDP2 have been reported in six patients from four unrelated pedigrees with spinocerebellar ataxia 23 (SCAR23). By whole-exome sequencing, we identified a novel TDP2 splice-site variant (c.636 + 3_636 + 6del) in two Italian siblings (aged 40 and 45) showing progressive ataxia, intellectual disability, speech delay, refractory seizures, and various physical anomalies. The variant caused exon 5 skipping with consequent nonsense-mediated mRNA decay and defective repair of TOP2-induced DSBs, as demonstrated by the functional assays on the patients' fibroblasts. Our findings further demonstrate the pathogenic role of TDP2 biallelic loss-of-function variants in SCAR23 pathogenesis. Considering the age of our patients, the oldest reported to date, and their extensive follow-up, our study delineates in more detail the clinical phenotype related to the loss of TDP2 activity.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc21019742
003      
CZ-PrNML
005      
20210830101333.0
007      
ta
008      
210728s2020 xxk f 000 0|eng||
009      
AR
024    7_
$a 10.1038/s10038-020-0800-4 $2 doi
035    __
$a (PubMed)32651480
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxk
100    1_
$a Errichiello, Edoardo $u Medical Genetics Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy. edoardo.errichiello@unipv.it
245    10
$a Characterization of a novel loss-of-function variant in TDP2 in two adult patients with spinocerebellar ataxia autosomal recessive 23 (SCAR23) / $c E. Errichiello, G. Zagnoli-Vieira, R. Rizzi, L. Garavelli, KW. Caldecott, O. Zuffardi
520    9_
$a TDP2 encodes a 5'-tyrosyl DNA phosphodiesterase required for the efficient repair of double-strand breaks (DSBs) induced by the abortive activity of DNA topoisomerase II (TOP2). To date, only three homozygous variants in TDP2 have been reported in six patients from four unrelated pedigrees with spinocerebellar ataxia 23 (SCAR23). By whole-exome sequencing, we identified a novel TDP2 splice-site variant (c.636 + 3_636 + 6del) in two Italian siblings (aged 40 and 45) showing progressive ataxia, intellectual disability, speech delay, refractory seizures, and various physical anomalies. The variant caused exon 5 skipping with consequent nonsense-mediated mRNA decay and defective repair of TOP2-induced DSBs, as demonstrated by the functional assays on the patients' fibroblasts. Our findings further demonstrate the pathogenic role of TDP2 biallelic loss-of-function variants in SCAR23 pathogenesis. Considering the age of our patients, the oldest reported to date, and their extensive follow-up, our study delineates in more detail the clinical phenotype related to the loss of TDP2 activity.
650    _2
$a dospělí $7 D000328
650    _2
$a DNA vazebné proteiny $x genetika $7 D004268
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a geny recesivní $x genetika $7 D005808
650    _2
$a lidé $7 D006801
650    _2
$a mentální retardace $x genetika $x patologie $7 D008607
650    _2
$a mutace ztráty funkce $x genetika $7 D000073658
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a lidé středního věku $7 D008875
650    _2
$a fosfodiesterasy $x genetika $7 D010727
650    _2
$a spinocerebelární ataxie $x genetika $x patofyziologie $7 D020754
655    _2
$a kazuistiky $7 D002363
655    _2
$a časopisecké články $7 D016428
700    1_
$a Zagnoli-Vieira, Guido $u Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, UK
700    1_
$a Rizzi, Romana $u Neurology Unit, Department of Neuro-Motor Diseases, Azienda USL-IRCCS Reggio Emilia, Reggio Emilia, Italy
700    1_
$a Garavelli, Livia $u Medical Genetics Unit, Department of Maternal and Child Health, Azienda USL-IRCCS Reggio Emilia, Reggio Emilia, Italy
700    1_
$a Caldecott, Keith W $u Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, UK $u Department of Genome Dynamics, Institute of Molecular Genetics of the ASCR, v.v.i, Prague, Czech Republic
700    1_
$a Zuffardi, Orsetta $u Medical Genetics Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy
773    0_
$w MED00005297 $t Journal of human genetics $x 1435-232X $g Roč. 65, č. 12 (2020), s. 1135-1141
856    41
$u https://pubmed.ncbi.nlm.nih.gov/32651480 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20210728 $b ABA008
991    __
$a 20210830101333 $b ABA008
999    __
$a ok $b bmc $g 1690532 $s 1140188
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2020 $b 65 $c 12 $d 1135-1141 $e 20200710 $i 1435-232X $m Journal of human genetics $n J Hum Genet $x MED00005297
LZP    __
$a Pubmed-20210728

Najít záznam

Citační ukazatele

Možnosti archivace