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

Abstract

Marinesco-Sjögren 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-Sjögren 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-Sjögren 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-Sjögren 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-Sjögren 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-Sjögren 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.

A nationwide survey on Marinesco-Sjögren syndrome in Japan

“…Skeletal muscle weakness is also a prominent characteristic. Almost all the MSS patients with SIL1 mutations in this series had muscle weakness initially noticed as a delayed motor milestone, which was detected at an earlier age than cataracts, as reported previously [3,15,16]. Regarding muscle biopsy, myopathic changes, including RV formation are a characteristic of patients with SIL1 mutations.…”

“…We could not exclude the possibility of the mutation occurred in the promoter or other non-coding region of SIL1 in these 3 patients. Previous reports also showed that approximately one-half of the MSS patients were genetically diagnosed as MSS from mutations in SIL1 [7,16]. The absence of RVs in the muscle biopsy tissue of one patient with no SIL1 mutation suggests the existence of a different disease mechanism(s) in such patients.…”

BiP and Its Nucleotide Exchange Factors Grp170 and Sil1: Mechanisms of Action and Biological Functions

“…In humans, mutations in the SIL1 gene have been found in over half the cases of M arinesco- S jögren s yndrome (MSS) 152–154 an autosomal recessive disease characterized by multisystem defects including cerebellar ataxia due to Purkinje cell loss, progressive myopathy, early onset cataracts, skeletal abnormalities, and a variety of developmental abnormalities and intellectual disabilities 155–158 . MSS-associated mutations occur throughout the SIL1 gene and most lead to the disruption of significant portions of the protein 98; 153; 155 , including those regions that interact with BiP.…”

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy

“…6,7 Marinesco-Sjögren syndrome (MSS [MIM:248800]) is a form of myopathy with a similar constellation of findings including muscle involvement, intellectual disability, cataracts, brain MRI findings, and other signs of central nervous system (CNS) involvement. 8,9 Cerebellar atrophy is often considered the most prominent neuroradiologic finding in MSS, but it is not an obligatory finding. 10 The clinical overlap can therefore make it difficult to distinguish between syndromic CMDs and MSS.…”