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000155599 1001_ $$0P:(DE-2719)9000375$$aMengel, David$$b0$$eFirst author
000155599 245__ $$aA de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype.
000155599 260__ $$aBerlin$$bSpringer$$c2021
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000155599 520__ $$aBiallelic STUB1 variants are a well-established cause of autosomal-recessive early-onset multisystemic ataxia (SCAR16). Evidence for STUB1 variants causing autosomal-dominant ataxia (SCA48) so far largely relies on segregation data in larger families. Presenting the first de novo occurrence of a heterozygous STUB1 variant, we here present additional qualitative evidence for STUB1-disease as an autosomal-dominant disorder.Whole exome sequencing on an index patient with sporadic early-onset ataxia, followed by Sanger sequencing in all family members, was used to identify causative variants as well as to rule out alternative genetic hits and intronic STUB1 variants. STUB1 mRNA and protein levels in PBMCs in all family members were analysed using qRT-PCR and Western Blot.A previously unreported start-lost loss-of-function variant c.3G>A in the start codon of STUB1 was identified in the index case, occurring de novo and without evidence for a second (potentially missed) variant (e.g., intronic or copy number) in STUB1. The patient showed an early adult-onset multisystemic ataxia complicated by spastic gait disorder, distal myoclonus and cognitive dysfunction, thus closely mirroring the systems affected in autosomal-recessive STUB1-associated disease. In line with the predicted start-lost effect of the variant, functional investigations demonstrated markedly reduced STUB1 protein expression in PBMCs, whereas mRNA levels were intact.De novo occurrence of the loss-of-function STUB1 variant in our case with multisystemic ataxia provides a qualitatively additional line of evidence for STUB1-disease as an autosomal-dominant disorder, in which the same neurological systems are affected as in its autosomal-recessive counterpart. Moreover, this finding adds support for loss-of-function as a mechanism underlying autosomal-dominant STUB1-disease, thus mirroring its autosomal-recessive counterpart also in terms of the underlying mutational mechanism.
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000155599 650_7 $$2Other$$aAtaxia
000155599 650_7 $$2Other$$aCHIP
000155599 650_7 $$2Other$$aDominant
000155599 650_7 $$2Other$$aEarly-onset ataxia
000155599 650_7 $$2Other$$aSCA48
000155599 650_7 $$2Other$$aSTUB1
000155599 650_2 $$2MeSH$$aAdult
000155599 650_2 $$2MeSH$$aAtaxia: genetics
000155599 650_2 $$2MeSH$$aCerebellar Ataxia
000155599 650_2 $$2MeSH$$aHumans
000155599 650_2 $$2MeSH$$aPedigree
000155599 650_2 $$2MeSH$$aPhenotype
000155599 650_2 $$2MeSH$$aSpinocerebellar Ataxias
000155599 650_2 $$2MeSH$$aUbiquitin-Protein Ligases: genetics
000155599 7001_ $$0P:(DE-2719)9000792$$aTraschuetz, Andreas$$b1$$udzne
000155599 7001_ $$0P:(DE-2719)2813732$$aReich, Selina$$b2
000155599 7001_ $$0P:(DE-2719)9001076$$aLeyva, Alejandra$$b3
000155599 7001_ $$0P:(DE-2719)2812792$$aBender, Friedemann$$b4
000155599 7001_ $$0P:(DE-2719)2810998$$aHauser, Stefan$$b5
000155599 7001_ $$aHaack, Tobias B$$b6
000155599 7001_ $$0P:(DE-2719)2811275$$aSynofzik, Matthis$$b7$$eLast author
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