title: Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco-Sjögren syndrome.
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.
authors.affiliation: Folkhälsan Institute of Genetics and Neuroscience Center, Department of Medical Genetics, University of Helsinki, Helsinki, Finland. anna-kaisa.anttonen@helsinki.fi
authors.forename: Anna-Kaisa
authors.initials: AK
authors.lastname: Anttonen
authors.forename: Eija
authors.initials: E
authors.lastname: Siintola
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Tranebjaerg
authors.forename: Nobue K
authors.initials: NK
authors.lastname: Iwata
authors.forename: Emilia K
authors.initials: EK
authors.lastname: Bijlsma
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Meguro
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Jun
authors.initials: J
authors.lastname: Goto
authors.forename: Outi
authors.initials: O
authors.lastname: Kopra
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005455:Fluorescent Antibody Technique; D006056:Golgi Apparatus / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013347:Subcellular Fractions
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D020662:Guanine Nucleotide Exchange Factors; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C418483:SIL1 protein, human