SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome

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dc.authoridWeis, Joachim/0000-0003-3280-6773|Claeys, Kristl/0000-0001-9937-443X|Baudis, Michael/0000-0002-9903-4248|Senderek, Jan/0000-0002-8263-1783|Benedicenti, Francesco/0000-0002-9458-0688|Kirschner, Janbernd/0000-0003-1618-7386|tay, stacey/0000-0002-3077-4184|Synofzik, Matthis/0000-0002-2280-7273
dc.contributor.authorKrieger, Michael
dc.contributor.authorRoos, Andreas
dc.contributor.authorStendel, Claudia
dc.contributor.authorClaeys, Kristl G.
dc.contributor.authorSonmez, Fatma Mujgan
dc.contributor.authorBaudis, Michael
dc.contributor.authorBauer, Peter
dc.date.accessioned2025-10-24T18:09:16Z
dc.date.available2025-10-24T18:09:16Z
dc.date.issued2013
dc.departmentMalatya Turgut Özal Üniversitesi
dc.description.abstractMarinesco-Sjogren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjogren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjogren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjogren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjogren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be missing in young children. As cognitive impairment is not obligatory, patients without intellectual disability but a Marinesco-Sjogren syndrome-compatible phenotype should receive SIL1 mutation analysis. Despite allelic heterogeneity and many families with private mutations, the phenotype related to SIL1 mutations is relatively homogenous. Based on SIL1 expression studies we speculate that this may arise from a uniform effect of different mutations on protein expression.
dc.description.sponsorshipMaximilian-May-Stiftung; Gebert-Ruf-Stiftung [GRS-046/09]; Else-Kroner-Fresenius-Stiftung [A59-09]
dc.description.sponsorshipThis work has been supported by grants from the Maximilian-May-Stiftung, the Gebert-Ruf-Stiftung (to J.S., grant no GRS-046/09) and the Else-Kroner-Fresenius-Stiftung (to A.R., grant no A59-09).
dc.identifier.doi10.1093/brain/awt283
dc.identifier.endpage3644
dc.identifier.issn0006-8950
dc.identifier.issn1460-2156
dc.identifier.pmid24176978
dc.identifier.scopus2-s2.0-84890589571
dc.identifier.scopusqualityQ1
dc.identifier.startpage3634
dc.identifier.urihttps://doi.org/10.1093/brain/awt283
dc.identifier.urihttps://hdl.handle.net/20.500.12899/3559
dc.identifier.volume136
dc.identifier.wosWOS:000328366000015
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherOxford Univ Press
dc.relation.ispartofBrain
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_20251023
dc.subjectMarinesco-Sjogren syndrome; ataxia; cataract; myopathy; SIL1 mutation
dc.titleSIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome
dc.title.alternativeSIL1 mutations and clinical spectrum in patients with Marinesco- Sjögren syndrome
dc.typeArticle

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