A novel SCARB2 mutation in progressive myoclonus epilepsy indicated by reduced β-glucocerebrosidase activity

Zeigler, Marsha; Meiner, Vardiella; Newman, J. P.; Steiner-Birmanns, Bettina; Bargal, Ruth; Sury, Vivi; Mengistu, Getu; Kakhlon, Or; leykin, Ina; Argov, Zohar; Abramsky, Oded; Lossos, Alexander

doi:10.1016/j.jns.2014.01.022

Cited by 22 publications

(16 citation statements)

References 16 publications

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“…20 Mutations in SCARB2 cause autosomal recessive progressive myoclonus epilepsy, in which reduced GBA activity is also noted. 78 Both SCARB2 and GBA are also strongly associated with another synucleinopathy, Lewy body dementia, [79][80][81] further supporting the effect of these genes on SNCA aggregation, and suggesting that SCARB2 variants may affect GBA and lysosomal function. It will be important to examine the effects of SCARB2 variants on transport of GBA to the lysosome and on its function in PD-relevant models.…”

Section: Gba-gaucher Diseasementioning

confidence: 90%

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

2015

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Section: Gba-gaucher Diseasementioning

confidence: 90%

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

2015

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“…Death ensued in all five patients (the only surviving patient at the time of the report died later). Since this initial report, other cases have been reported and the clinical features of PME without renal failure associated with SCARB2 have been described (Rubboli et al ., ; Guerrero‐López et al ., ; Higashiyama et al ., ; Fu et al ., ; Zeigler et al ., ). Features seen in these patients included a variable severity of epilepsy: from uncontrolled seizures or status epilepticus with prominent photosensitivity in patients with adolescent onset, to infrequent or no major seizures in patients with a more delayed onset (Rubboli et al ., ), late onset in adulthood (Higashiyama et al ., ; Fu et al ., ), and the occurrence of dementia (Fu et al ., ).…”

Section: Clinical Features Of Action Myoclonus Renal Failurementioning

confidence: 99%

SCARB2/LIMP2 deficiency in action myoclonus‐renal failure syndrome

Dibbens¹,

Schwake²,

Säftig³

et al. 2016

Epileptic Disorders

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Action myoclonus–renal failure syndrome (AMRF) is an autosomal recessive progressive myoclonus epilepsy (PME) associated with renal dysfunction that appears in the second or third decade of life and that is caused by loss‐of‐function mutations in the SCARB2 gene encoding lysosomal integral membrane protein type 2 (LIMP2). Recent reports have documented cases with PME associated with SCARB2 mutations without renal compromise. Additional neurological features can be demyelinating peripheral neuropathy, hearing loss and dementia. The course of the disease in relentlessly progressive. In this paper we provide an updated overview of the clinical and genetic features of SCARB2‐related PME and on the functions of the LIMP2 protein.

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“… 1 , 2 The scavenger receptor class B member 2 ( SCARB2 ) gene encodes a protein, lysosome membrane protein 2 (LIMP-2), that transports β-glucocerebrosidase (GCase) from the endoplasmic reticulum through the Golgi apparatus and endosomes to the lysosome. 3 Homozygous mutations in SCARB2 cause a rare form of progressive myoclonic epilepsy, action myoclonus-renal failure. 3 Affected patients have significantly reduced GCase activity (7 nmol/mg protein per h compared with 15 nmol/mg protein per h in controls), 3 , 4 that is in the range observed for carriers of Gaucher disease ( GBA heterozygotes).…”

Section: Introductionmentioning

confidence: 99%

SCARB2 variants and glucocerebrosidase activity in Parkinson’s disease

Alcalay

Levy

Wolf³

et al. 2016

npj Parkinson's Disease

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Mutations in glucocerebrosidase (GBA) are a common risk factor for Parkinson's disease (PD). The scavenger receptor class B member 2 (SCARB2) gene encodes a receptor responsible for the transport of glucocerebrosidase (GCase) to the lysosome. Two common SNPs in linkage disequilibrium with SCARB2, rs6812193 and rs6825004, have been associated with PD and Lewy Body Disease in genome-wide association studies. Whether these SNPs are associated with altered glucocerebrosidase enzymatic activity is unknown. Our objective was to determine whether SCARB2 SNPs are associated with PD and with reduced GCase activity. The GBA gene was fully sequenced, and the LRRK2 G2019S and SCARB2 rs6812193 and rs6825004 SNPs were genotyped in 548 PD patients and 272 controls. GCase activity in dried blood spots was measured by tandem mass spectrometry. We tested the association between SCARB2 genotypes and PD risk in regression models adjusted for gender, age, and LRRK2 G2019S and GBA mutation status. We compared GCase activity between participants with different genotypes at rs6812193 and rs6825004. Genotype at rs6812193 was associated with PD status. PD cases were less likely to carry the T allele than the C allele (OR=0.71; P=0.004), but GCase enzymatic activity was similar across rs6812193 genotypes (C/C: 11.88 μmol/l/h; C/T: 11.80 μmol/l/h; T/T: 12.02 μmol/l/h; P=0.867). Genotype at rs6825004 was not associated with either PD status or GCase activity. In conclusion, our results support an association between SCARB2 genotype at rs6812193 and PD, but suggest that the increased risk is not mediated by GCase activity.

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A novel SCARB2 mutation in progressive myoclonus epilepsy indicated by reduced β-glucocerebrosidase activity

Cited by 22 publications

References 16 publications

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

SCARB2/LIMP2 deficiency in action myoclonus‐renal failure syndrome

SCARB2 variants and glucocerebrosidase activity in Parkinson’s disease

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