TY  - JOUR
AU  - Mengel, David
AU  - Traschuetz, Andreas
AU  - Reich, Selina
AU  - Leyva, Alejandra
AU  - Bender, Friedemann
AU  - Hauser, Stefan
AU  - Haack, Tobias B
AU  - Synofzik, Matthis
TI  - A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype.
JO  - Journal of neurology
VL  - 268
IS  - 10
SN  - 0340-5354
CY  - Berlin
PB  - Springer
M1  - DZNE-2021-00767
SP  - 3845-3851
PY  - 2021
N1  - ISSN 1432-1459 not unique: **2 hits**.
AB  - Biallelic 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.
KW  - Adult
KW  - Ataxia: genetics
KW  - Cerebellar Ataxia
KW  - Humans
KW  - Pedigree
KW  - Phenotype
KW  - Spinocerebellar Ataxias
KW  - Ubiquitin-Protein Ligases: genetics
KW  - Ataxia (Other)
KW  - CHIP (Other)
KW  - Dominant (Other)
KW  - Early-onset ataxia (Other)
KW  - SCA48 (Other)
KW  - STUB1 (Other)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC8463406
C6  - pmid:33811518
DO  - DOI:10.1007/s00415-021-10524-7
UR  - https://pub.dzne.de/record/155599
ER  -