Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco-Sjögren syndrome.
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.
Anttonen
Anna-Kaisa
AK
Folkhälsan Institute of Genetics and Neuroscience Center, Department of Medical Genetics, University of Helsinki, Helsinki, Finland. anna-kaisa.anttonen@helsinki.fi
Siintola
Eija
E
Tranebjaerg
Lisbeth
L
Iwata
Nobue K
NK
Bijlsma
Emilia K
EK
Meguro
Hiroyuki
H
Ichikawa
Yaeko
Y
Goto
Jun
J
Kopra
Outi
O
Lehesjoki
Anna-Elina
AE
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
D000091342:Endoplasmic Reticulum Chaperone BiP; D020662:Guanine Nucleotide Exchange Factors; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C418483:SIL1 protein, human