1. ¹Folkhälsan Institute of Genetics and Neuroscience Center, University of Helsinki, Helsinki, Finland
2. ²Department of Medical Genetics, University of Helsinki, Helsinki, Finland
3. ³Department of Medical Genetics, University Hospital of Tromsoe, Tromsoe, Norway
4. ⁴Department of Audiology, H:S Bispebjerg Hospital, and Institute of Medical Biochemistry and Genetics IMBG, Wilhelm Johannsen Centre of Functional Genomics, University of Copenhagen, Copenhagen, Denmark
5. ⁵Department of Neurology, Division of Neuroscience, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
6. ⁶Department of Clinical Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
7. ⁷Department of Internal Medicine, Niigata Central Hospital, Niigata, Japan

Correspondence: Dr A-K Anttonen, Department of Medical Genetics, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland. Tel: +358 9 191 25090; Fax: +358 9 191 25073; E-mail: anna-kaisa.anttonen@helsinki.fi

Received 15 November 2007; Revised 17 January 2008; Accepted 17 January 2008; Published online 20 February 2008.

Abstract

Marinesco–Sjögren syndrome (MSS) is a rare autosomal recessively inherited neurodegenerative disorder characterized by cerebellar ataxia, cataracts, mental retardation, and progressive myopathy. Recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum (ER) resident cochaperone, were identified as a major cause of MSS. We here report four novel mutations in SIL1, including the first missense substitution p.Leu457Pro described in MSS. In addition, we excluded three functional candidate genes, HSPA5, HYOU1, and AARS, as causative genes in SIL1 mutation-negative patients. To understand the mechanisms of disturbed SIL1 function, we studied the subcellular localization of the missense mutant Leu457Pro protein in COS-1 cells. Moreover, we studied a mutant protein lacking the putative C-terminal ER retrieval signal. In contrast to the wild-type protein's localization to ER and Golgi apparatus, both mutant proteins formed aggregates within the ER depending on the expression level. These data imply that aggregation of mutant proteins may contribute to MSS pathogenesis. The genetic background of a subgroup of patients with MSS remains uncovered.