Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16
| Autor: | Adrienne Sexton, Stefan Johansson, Bryony A. Thompson, Yasaman Pakdaman, Siren Berland, Sigrid Erdal, Ståle Ellingsen, Helene J. Bustad, Ingvild Aukrust, Paul A. James, Laurence A. Bindoff, Martin Krooni, Per M. Knappskog, Line Iden Berge, Kjersti Nesheim Power |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Protein Folding Gene Expression 0302 clinical medicine spinocerebellar ataxia SCA48 Biology (General) Age of Onset Spectroscopy Genes Dominant Genetics CHIP General Medicine Middle Aged Phenotype Computer Science Applications Ubiquitin ligase Pedigree Chemistry E3 ubiquitin ligase Frontotemporal Dementia Spinocerebellar ataxia Cerebellar atrophy Female medicine.symptom Adult Heterozygote Ataxia QH301-705.5 Ubiquitin-Protein Ligases Genes Recessive Biology Catalysis Article Inorganic Chemistry 0399 Other Chemical Sciences 0604 Genetics 0699 Other Biological Sciences 03 medical and health sciences medicine Humans Spinocerebellar Ataxias Family Physical and Theoretical Chemistry QD1-999 Molecular Biology Aged STUB1 Chemical Physics Organic Chemistry SCAR16 Heterozygote advantage medicine.disease 030104 developmental biology Cerebellar cognitive affective syndrome Mutation biology.protein 030217 neurology & neurosurgery |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 22, Iss 5870, p 5870 (2021) Volume 22 Issue 11 |
| Popis: | Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases. |
| Databáze: | OpenAIRE |
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