Universität zu Köln

Smets, Katrien, Deconinck, Tine, Baets, Jonathan, Sieben, Anne, Martin, Jean-Jacques, Smouts, Iris, Wang, Shuaiyu, Taroni, Franco ORCID: 0000-0002-2420-5233, Di Bella, Daniela ORCID: 0000-0003-0912-5136, Van Hecke, Wim, Parizel, Paul M. ORCID: 0000-0002-0221-2854, Jadoul, Christina, De Potter, Robert, Couvreur, Francine, Rugarli, Elena ORCID: 0000-0002-5782-1067 and De Jonghe, Peter (2014). Partial deletion of AFG3L2 causing spinocerebellar ataxia type 28. Neurology, 82 (23). S. 2092 - 2101. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1526-632X

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Abstract

Objective: To identify the genetic cause of autosomal dominant spinocerebellar ataxia type 28 (SCA28) with ptosis in 2 Belgian families without AFG3L2 point mutations and further extend the clinical spectrum of SCA28 through the study of a brain autopsy, advanced MRI, and cell-based functional assays exploring the underlying disease mechanism. Methods: Two large families were clinically examined in detail. Linkage analysis and multiplex amplicon quantification were performed. A brain autopsy was obtained. Brain MRI with voxel-based morphometry and diffusion tensor imaging was performed. RNA and Western blot analysis and blue native-polyacrylamide gel electrophoresis experiments were performed. Results: MRI analysis demonstrated a significant cerebellar atrophy, as well as white matter degeneration in the cerebellar peduncles, corticospinal tracts, corpus callosum, and cingulum. A brain autopsy showed severe atrophy of the upper part of the cerebellar hemisphere. Ubiquitin and p62 immunoreactive intranuclear inclusions were found in cerebral and cerebellar cortical neurons, in neurons of the hippocampus, and in pontine and medullary nuclei. An identical heterozygous partial deletion of exons 14 to 16 of the AFG3L2 gene was found in both families. Additional functional assays in patient-derived cell lines revealed haploinsufficiency as the underlying disease mechanism. Conclusions: Our study expands the phenotypic characterization of SCA28 by means of brain pathology and diffusion tensor imaging/voxel-based morphometry MRIs. The identification of a partial AFG3L2 deletion and the subsequent functional studies reveal loss of function as the most likely disease mechanism. Specific testing for deletions in AFG3L2 is warranted because these escape standard sequencing.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Smets, Katrien UNSPECIFIED UNSPECIFIED UNSPECIFIED Deconinck, Tine UNSPECIFIED UNSPECIFIED UNSPECIFIED Baets, Jonathan UNSPECIFIED UNSPECIFIED UNSPECIFIED Sieben, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Martin, Jean-Jacques UNSPECIFIED UNSPECIFIED UNSPECIFIED Smouts, Iris UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Shuaiyu UNSPECIFIED UNSPECIFIED UNSPECIFIED Taroni, Franco UNSPECIFIED orcid.org/0000-0002-2420-5233 UNSPECIFIED Di Bella, Daniela UNSPECIFIED orcid.org/0000-0003-0912-5136 UNSPECIFIED Van Hecke, Wim UNSPECIFIED UNSPECIFIED UNSPECIFIED Parizel, Paul M. UNSPECIFIED orcid.org/0000-0002-0221-2854 UNSPECIFIED Jadoul, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED De Potter, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Couvreur, Francine UNSPECIFIED UNSPECIFIED UNSPECIFIED Rugarli, Elena UNSPECIFIED orcid.org/0000-0002-5782-1067 UNSPECIFIED De Jonghe, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-435870
DOI:	10.1212/WNL.0000000000000491
Journal or Publication Title:	Neurology
Volume:	82
Number:	23
Page Range:	S. 2092 - 2101
Date:	2014
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1526-632X
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DOMINANT CEREBELLAR-ATAXIA; SLOW PROGRESSION; SPASTIC PARAPLEGIA; MUTATIONS; ONSET; SCA28 Multiple languages Clinical Neurology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/43587