SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome
| Autor: | Dorothea Wand, Petra Muschke, M. Krieger, Martin Häussler, Haluk Topaloglu, Francesco Benedicenti, Franco Stanzial, Laura Pirra, Fatma Mujgan Sonmez, Sabine Rudnik-Schöneborn, Helen Kingston, Stacey K.H. Tay, Francesca Inzana, Janbernd Kirschner, Denise Williams, Sabrina Spengler, Claudia Stendel, Richard S. Finkel, Kristl G. Claeys, Peter Bauer, Andreas Dufke, Ana Lia Taratuto, Antje Bornemann, Andreas Roos, Hans H. Goebel, Jan Senderek, Michael Baudis, Joachim Weis, Christian de Goede, Klaus Zerres, François Rivier, Gökhan Uyanik, Matthis Synofzik, Livija Medne |
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| Přispěvatelé: | Çocuk Sağlığı ve Hastalıkları, University of Zurich, Senderek, Jan |
| Rok vydání: | 2013 |
| Předmět: |
Male
Pathology medicine.medical_specialty Ataxia ultrastructure [Muscle Skeletal] SIL1 protein human Adolescent Marinesco–Sjögren syndrome DNA Mutational Analysis genetics [Mutation] Bioinformatics medicine.disease_cause pathology [Muscle Skeletal] physiopathology [Spinocerebellar Degenerations] Cataracts pathology [Brain] Intellectual disability medicine Guanine Nucleotide Exchange Factors Humans ddc:610 Myopathy Muscle Skeletal Cells Cultured Retrospective Studies Spinocerebellar Degenerations Family Health Mutation B-Lymphocytes Cerebellar ataxia business.industry Brain medicine.disease genetics [Guanine Nucleotide Exchange Factors] Magnetic Resonance Imaging 10124 Institute of Molecular Life Sciences genetics [Spinocerebellar Degenerations] 2728 Neurology (clinical) pathology [Spinocerebellar Degenerations] ultrastructure [Brain] 570 Life sciences biology Allelic heterogeneity Female Neurology (clinical) Neurosciences & Neurology medicine.symptom business |
| Zdroj: | Brain 136(12), 3634-3644 (2013). doi:10.1093/brain/awt283 |
| ISSN: | 1460-2156 |
| Popis: | Marinesco-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. |
| Databáze: | OpenAIRE |
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