Thomas Roux1, Mathieu Barbier1, Mélanie Papin1,2, Claire-Sophie Davoine1,2, Sabrina Sayah1, Giulia Coarelli1, Perrine Charles3, Cecilia Marelli4, Livia Parodi1, Christine Tranchant5, Cyril Goizet6, Stephan Klebe7, Ebba Lohmann8, Lionel Van Maldergem9, Christine van Broeckhoven10, Marie Coutelier1,2, Christelle Tesson1, Giovanni Stevanin1,2, Charles Duyckaerts1, Alexis Brice1, Alexandra Durr11. 1. Sorbonne Université, Institut du Cerveau-Paris Brain Institute (ICM), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, Paris, France. 2. EPHE, PSL Research University, Neurogenetics Group, Paris, France. 3. Genetic Department, University Hospital Pitié-Salpêtrière, AP-HP, Paris, France. 4. Expert center for Neurogenetic Diseases, Department of Neurology, CHU Gui de Chauliac, MMDN, Univ Montpellier, INSERM, EPHE, Montpellier, France. 5. Neurological Department University Hospital Strasbourg, Strasbourg, France. 6. University Bordeaux, Laboratoire MRGM, INSERM U1211, Centre de Référence Neurogénétique, Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France. 7. University Hospital Essen, Department of Neurology, Essen, Germany. 8. Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. 9. Université de Franche-Comté, Centre de Génétique Humaine, Centre Hospitalier Régional Universitaire, Besançon, France. 10. Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, Laboratory of Neurogenetics, Institute Born-Bunge and Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. 11. Sorbonne Université, Institut du Cerveau-Paris Brain Institute (ICM), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, Paris, France. alexandra.durr@icm-institute.org.
Abstract
PURPOSE: Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48). METHODS: We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance. RESULTS: STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease-like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) "second hits" in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects. CONCLUSION: Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.
PURPOSE: Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48). METHODS: We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance. RESULTS: STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease-like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) "second hits" in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects. CONCLUSION: Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.
Authors: A Umano; K Fang; Z Qu; J B Scaglione; S Altinok; C J Treadway; E T Wick; E Paulakonis; C Karunanayake; S Chou; T M Bardakjian; P Gonzalez-Alegre; R C Page; J C Schisler; N G Brown; D Yan; K M Scaglione Journal: J Biol Chem Date: 2022-04-07 Impact factor: 5.486
Authors: Marlen Colleen Reis; Julia Patrun; Nibal Ackl; Pia Winter; Maximilian Scheifele; Adrian Danek; Dagmar Nolte Journal: Front Mol Neurosci Date: 2022-04-14 Impact factor: 5.639
Authors: Yasaman Pakdaman; Siren Berland; Helene J Bustad; Sigrid Erdal; Bryony A Thompson; Paul A James; Kjersti N Power; Ståle Ellingsen; Martin Krooni; Line I Berge; Adrienne Sexton; Laurence A Bindoff; Per M Knappskog; Stefan Johansson; Ingvild Aukrust Journal: Int J Mol Sci Date: 2021-05-30 Impact factor: 5.923