Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco–Sjögren syndrome

Anttonen, Anna‐Kaisa; Siintola, Eija; Tranebjærg, Lisbeth; Iwata, Nobuyoshi; Bijlsma, Emilia K.; Meguro, Hiroyuki; Ichikawa, Yaeko; Goto, Jun; Kopra, Outi; Lehesjoki, Anna‐Elina

doi:10.1038/ejhg.2008.22

Cited by 40 publications

(43 citation statements)

References 21 publications

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“…More recent studies have suggested that the KDEL receptor can recognize a large number of variations on this sequence 97 , and thus due to the highly conserved nature of the KELR tetrapeptide, it was assumed that it represented a divergent ER retention sequence 5 . Instead, it was recently revealed that this conserved sequence plays a critical role in structural integrity of the human Sil1 protein 98; 99 . These residues are likely to form tertiary interactions with other portions of the protein that serve to stabilize an otherwise weak α-helix at the C-terminus 99 .…”

Section: Regulating the Atpase Cycle Of Bip In The Er Environment mentioning

confidence: 99%

“…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. However, three MSS-associated mutations have been identified that disrupt only the last 4 or 5 amino acids of Sil1, which affects its solubility and stability resulting in significantly diminished expression of these Sil1 mutants 98; 99 .…”

Section: Contribution Of Er Nefs To Biological Functionsmentioning

confidence: 99%

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

Behnke

Feige

Hendershot

2015

Journal of Molecular Biology

164

168

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BiP is the endoplasmic reticulum (ER) orthologue of the Hsp70 family of molecular chaperones and is intricately involved in most functions of this organelle through its interactions with a variety of substrates and regulatory proteins. Like all Hsp70 family members, the ability of BiP to bind and release unfolded proteins is tightly regulated by a cycle of ATP binding, hydrolysis, and nucleotide exchange. As a characteristic of the Hsp70 family, multiple DnaJ-like co-factors exist that can target substrates to BiP and stimulate its ATPase activity to stabilize the binding of BiP to substrates. However, only in the past decade have nucleotide exchange factors (NEFs) for BiP been identified, which has shed light not only on the mechanism of BiP assisted folding in the ER but also on Hsp70 family members that reside throughout the cell. We will review the current understanding of the ATPase cycle of BiP in the unique environment of the ER and how it is regulated by the NEFs, Grp170 and Sil1, both of which perform unanticipated roles in various biological functions and disease states.

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Section: Regulating the Atpase Cycle Of Bip In The Er Environment mentioning

confidence: 99%

Section: Contribution Of Er Nefs To Biological Functionsmentioning

confidence: 99%

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

Behnke

Feige

Hendershot

2015

Journal of Molecular Biology

164

168

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“…98 The responsible gene is SIL1 on chromosome 5 which encodes a nucleotide exchange factor for the heat shock protein 70 chaperone HSPA5. 99 A defect in SIL1 function leads to the accumulation of potentially cytotoxic unfolded proteins. 100 Although SIL1 is the only gene associated with MSS, some patients with the typical MSS phenotype have been reported without SIL1 mutations.…”

Section: Inherited Ataxiasmentioning

confidence: 99%

Ataxia

Akbar

Ashizawa

2015

Neurologic Clinics

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Balance and coordination are products of complex circuitry involving the basal ganglia, cerebellum and cerebral cortex, as well as peripheral motor and sensory pathways. Malfunction of any part of this intricate circuitry can lead to imbalance and incoordination, or ataxia, of gait, the limbs or eyes, or a combination thereof. Ataxia can be a symptom of a multisystemic disorder, or it can manifest as the major component of a disease process. Ongoing discoveries of genetic abnormalities suggest the role ofmitochondrial dysfunction, oxidative stress, abnormal mechanisms of DNA repair, possible protein misfolding, and abnormalities in cytoskeletal proteins. Few ataxias are fully treatable, and most are symptomatically managed. A discussion of the ataxias is presented here with brief mention of acquired ataxias, and a greater focus on inherited ataxias.

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“…Further novel mutations in the SIL1 gene in MSS were subsequently identified. [7][8][9] Although mutations in the SIL1 gene account for the majority of MSS cases, Senderrek et al 5 reported four individuals with typical MSS lacking SIL1 mutations. These reports suggest genetic heterogeneity in MSS.…”

Section: Introductionmentioning

confidence: 99%

Novel mutations in the SIL1 gene in a Japanese pedigree with the Marinesco–Sjögren syndrome

Takahata

Yamada

et al. 2010

J Hum Genet

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Marinesco-Sjö gren syndrome (MSS) is a rare autosomal recessive disorder. Mutation in the SIL1 gene accounts for the majority of MSS cases. However, some individuals with typical MSS without SIL1 mutations have been reported. In this study, we identified two novel mutations in a Japanese pedigree with MSS, one of which was an intragenic deletion not detected using the PCR-direct sequencing protocol. This family consisted of three affected siblings, an unaffected sibling and unaffected parents. We found a homozygous 5-bp deletion, del598-602(GAAGA), in exon 6 of all affected siblings by PCR. Thus, we expected that both parents would be heterozygous for the mutation. As expected, the father was heterozygous, whereas the mother demonstrated no mutations. We then carried out array comparative genomic hybridization and quantitative PCR analyses, and identified an approximately 58 kb deletion in exon 6 in the patients and mother. As a result, the mother was hemizygous for a 58-kb deletion. The affected siblings contained two mutations, a 5-bp and a 58-kb deletion, resulting in SIL1 gene dysfunction. It is possible that some reported cases of MSS without base alterations in the SIL1 gene are caused by deletions rather than locus heterogeneity.

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Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco–Sjögren syndrome

Cited by 40 publications

References 21 publications

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

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

Ataxia

Novel mutations in the SIL1 gene in a Japanese pedigree with the Marinesco–Sjögren syndrome

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