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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Accession codes
References
Lagier-Tourenne C, Tranebaerg L, Chaigne D et al: Homozygosity mapping of Marinesco–Sjogren syndrome to 5q31. Eur J Hum Genet 2003; 11: 770–778.
Marinesco G, Draganesco S, Vasiliu D : Nouvelle maladie familiale caractérisée par une cataracte congénitale et un arrêt du développement somato-neuro-psychique. Encéphale 1931; 26: 97–109.
Sjögren T : Hereditary congenital spinocerebellar ataxia accompanied by congenital cataract and oligophrenia. Confin Neurol 1950; 10: 293–308.
Anttonen AK, Mahjneh I, Hamalainen RH et al: The gene disrupted in Marinesco–Sjogren syndrome encodes SIL1, an HSPA5 cochaperone. Nat Genet 2005; 37: 1309–1311.
Senderek J, Krieger M, Stendel C et al: Mutations in SIL1 cause Marinesco–Sjogren syndrome, a cerebellar ataxia with cataract and myopathy. Nat Genet 2005; 37: 1312–1314.
Annesi G, Aguglia U, Tarantino P et al: SIL1 and SARA2 mutations in Marinesco–Sjogren and chylomicron retention diseases. Clin Genet 2007; 71: 288–289.
Karim MA, Parsian AJ, Cleves MA et al: A novel mutation in BAP/SIL1 gene causes Marinesco–Sjogren syndrome in an extended pedigree. Clin Genet 2006; 70: 420–423.
Chung KT, Shen Y, Hendershot LM : BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP. J Biol Chem 2002; 277: 47557–47563.
Tyson JR, Stirling CJ : LHS1 and SIL1 provide a lumenal function that is essential for protein translocation into the endoplasmic reticulum. EMBO J 2000; 19: 6440–6452.
Hendershot LM : The ER function BiP is a master regulator of ER function. Mt Sinai J Med 2004; 71: 289–297.
Zhao L, Longo-Guess C, Harris BS, Lee JW, Ackerman SL : Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP. Nat Genet 2005; 37: 974–979.
Todorov A : [Marinesco–Sjogren syndrome. 1st anatomo-clinical study]. J Genet Hum 1965; 14: 197–233.
Mahloudji M, Amirhakimi GH, Haghighi P, Khodadoust AA : Marinesco–Sjogren syndrome. Report of an autopsy. Brain 1972; 95: 675–680.
Skre H, Berg K : Linkage studies on Marinesco–Sjogren syndrome and hypergonadotropic hypogonadism. Clin Genet 1977; 11: 57–66.
Lee JW, Beebe K, Nangle LA et al: Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration. Nature 2006; 443: 50–55.
Weitzmann A, Volkmer J, Zimmermann R : The nucleotide exchange factor activity of Grp170 may explain the non-lethal phenotype of loss of Sil1 function in man and mouse. FEBS Lett 2006; 580: 5237–5240.
Zoghbi HY, Orr HT : Glutamine repeats and neurodegeneration. Annu Rev Neurosci 2000; 23: 217–247.
Andersen B : Marinesco–Sjoegren Syndrome: Spinocerebellar Ataxia, Congenital Cataract, Somatic and Mental Retardation. Dev Med Child Neurol 1965; 47: 249–257.
Torbergsen T, Aasly J, Borud O, Lindal S, Mellgren SI : Mitochondrial myopathy in Marinesco–Sjogren syndrome. J Ment Defic Res 1991; 35 (Part 2): 154–159.
Maquat LE : Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol 2004; 5: 89–99.
Lewis MJ, Pelham HR : Ligand-induced redistribution of a human KDEL receptor from the Golgi complex to the endoplasmic reticulum. Cell 1992; 68: 353–364.
Munro S, Pelham HR : A C-terminal signal prevents secretion of luminal ER proteins. Cell 1987; 48: 899–907.
Steel GJ, Fullerton DM, Tyson JR, Stirling CJ : Coordinated activation of Hsp70 chaperones. Science 2004; 303: 98–101.
Ni M, Lee AS : ER chaperones in mammalian development and human diseases. FEBS Lett 2007; 581: 3641–3651.
Acknowledgements
We thank the patients, their families, and referring clinicians for collaboration. Hanna Olanne, Ann-Liz Träskelin, and Mira Aronen are thanked for their excellent technical assistance. Professor Michel Koenig, Dr Clotilde Lagier-Tourenne, Dr Ibrahim Mahjneh, Dr Riikka Hämäläinen, Dr Tarja Joensuu, and Dr Ulla Lahtinen are thanked for help and advice. Dr EAJ Peeters is thanked for providing clinical data on patient M2003. This study was supported by the Folkhälsan Research Foundation and the Center of Excellence in Complex Disease Genetics of the Academy of Finland for A-EL, and by the Biomedicum Helsinki Foundation, Emil Aaltonen Foundation, Finnish Medical Foundation, and Neurologiasäätiö for A-KA. A-KA and ES are fellows of the Helsinki Biomedical Graduate School.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Anttonen, AK., Siintola, E., Tranebjaerg, L. et al. Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco–Sjögren syndrome. Eur J Hum Genet 16, 961–969 (2008). https://doi.org/10.1038/ejhg.2008.22
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/ejhg.2008.22
Keywords
This article is cited by
-
A Review of Brain and Pituitary Gland MRI Findings in Patients with Ataxia and Hypogonadism
The Cerebellum (2023)
-
Novel Ocular Features in a Child with Marinesco-Sjögren Syndrome: Case Report and Literature Review
SN Comprehensive Clinical Medicine (2021)
-
Ataxia in children: early recognition and clinical evaluation
Italian Journal of Pediatrics (2017)
-
Cellular Signature of SIL1 Depletion: Disease Pathogenesis due to Alterations in Protein Composition Beyond the ER Machinery
Molecular Neurobiology (2016)
-
The nucleotide exchange factor SIL1 is required for glucose-stimulated insulin secretion from mouse pancreatic beta cells in vivo
Diabetologia (2014)
