Spinocerebellar ataxia type 17-digenic TBP/STUB1 disease: neuropathologic features of an autopsied patient

Rie Saito; Yui Tada; Daisuke Oikawa; Yusuke Sato; Makiko Seto; Akira Satoh; Kodai Kume; Nozomi Ueki; Masahiro Nakashima; Shintaro Hayashi; Yasuko Toyoshima; Fuminori Tokunaga; Hideshi Kawakami; Akiyoshi Kakita

doi:10.1186/s40478-022-01486-6

Spinocerebellar ataxia type 17-digenic TBP/STUB1 disease: neuropathologic features of an autopsied patient

Acta Neuropathol Commun. 2022 Dec 7;10(1):177. doi: 10.1186/s40478-022-01486-6.

Authors

Rie Saito¹, Yui Tada², Daisuke Oikawa³, Yusuke Sato⁴, Makiko Seto⁵, Akira Satoh⁵, Kodai Kume², Nozomi Ueki⁶, Masahiro Nakashima⁶, Shintaro Hayashi^{1

7}, Yasuko Toyoshima^{1

8}, Fuminori Tokunaga³, Hideshi Kawakami², Akiyoshi Kakita^{9

10}

Affiliations

¹ Departments of Pathology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Chuo-ku, Niigata, 951-8585, Japan.
² Department of Molecular Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
³ Department of Medical Biochemistry, Graduate School of Medicine, Osaka Metropolitan University, 1- 4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.
⁴ Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-cho Minami, Tottori, 680-8552, Japan.
⁵ Section of Neurology, Nagasaki Kita Hospital, 800 Motomurago, Togitsu-cho, Nishisonogi-gun, Nagasaki, 851-2103, Japan.
⁶ Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
⁷ Department of Neurology, Mishima Hospital, 1713-8, Fujikawa, Nagaoka, Niigata, 940-2302, Japan.
⁸ Department of Neurology, Brain Disease Center, Agano Hospital, 6317-5, Yasuda, Agano, Niigata, 959- 2221, Japan.
⁹ Departments of Pathology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Chuo-ku, Niigata, 951-8585, Japan. kakita@bri.niigata-u.ac.jp.
¹⁰ Department of Pathology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Chuo-ku, Niigata, 951-8585, Japan. kakita@bri.niigata-u.ac.jp.

Abstract

Spinocerebellar ataxia (SCA) type 17-digenic TBP/STUB1 disease (SCA17-DI) has been recently segregated from SCA17, caused by digenic inheritance of two gene mutations - intermediate polyglutamine-encoding CAG/CAA repeat expansions (polyQ) in TBP (TBP_{41 - 49}) and STUB1 heterozygosity - the former being associated with SCA17, and the latter with SCA48 and SCAR16 (autosomal recessive). In SCA17, most patients carry intermediate TBP_{41 - 49} alleles but show incomplete penetrance, and the missing heritability can be explained by a new entity whereby TBP_{41 - 49} requires the STUB1 variant to be symptomatic. The STUB1 gene encodes the chaperone-associated E3 ubiquitin ligase (CHIP) involved in ubiquitin-mediated proteasomal control of protein homeostasis. However, reports of the neuropathology are limited and role of STUB1 mutations in SCA17-DI remain unknown. Here we report the clinicopathologic features of identical twin siblings, one of whom was autopsied and was found to carry an intermediate allele (41 and 38 CAG/CAA repeats) in TBP and a heterozygous missense mutation in STUB1 (p.P243L). These patients developed autosomal recessive Huntington's disease-like symptoms. Brain MRI showed diffuse atrophy of the cerebellum and T2WI revealed hyperintense lesions in the basal ganglia and periventricular deep white matter. The brain histopathology of the patient shared features characteristic of SCA17, such as degeneration of the cerebellar cortex and caudate nucleus, and presence of 1C2-positive neurons. Here we show that mutant CHIP fails to generate the polyubiquitin chain due to disrupted folding of the entire U box domain, thereby affecting the E3 activity of CHIP. When encountering patients with cerebellar ataxia, especially those with Huntington's disease-like symptoms, genetic testing for STUB1 as well as TBP should be conducted for diagnosis of SCA17-DI, even in cases of sporadic or autosomal recessive inheritance.

Keywords: Huntington’s disease-like symptoms; Neuropathology; SCA17-DI; STUB1; TBP; polyQ stretch.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autopsy
Humans
Huntington Disease*
Neuropathology
Spinocerebellar Ataxias* / genetics
Ubiquitin-Protein Ligases / genetics

Substances

STUB1 protein, human
Ubiquitin-Protein Ligases