A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome

Abstract

The main clinical features of two siblings from a consanguineous marriage were progressive myoclonic epilepsy without intellectual impairment and a nephrotic syndrome with a strong accumulation of C1q in capillary loops and mesangium of kidney. The biochemical analysis of one of the patients revealed a normal beta-glucocerebrosidase activity in leukocytes, but a severe enzymatic deficiency in cultured skin fibroblasts. This deficiency suggested a defect in the intracellular sorting pathway of this enzyme. The sequence analysis of the gene encoding LIMP-2 (SCARB2), the sorting receptor for beta-glucocerebrosidase, confirmed this hypothesis. A homozygous nonsense mutation in codon 178 of SCARB2 was found in the patient, whereas her healthy parents were heterozygous for the mutation. Besides lacking immunodetectable LIMP-2, patient fibroblasts also had decreased amounts of beta-glucocerebrosidase, which was mainly located in the endoplasmic reticulum, as assessed by its sensitivity to Endo H. This is the first report of a mutation in the SCARB2 gene associated with a human disease, which, contrary to earlier proposals, shares no features with Charcot-Marie-Tooth disease both at the clinical and neurophysiological levels.

Antiviral activity of acid beta-glucosidase 1 on enterovirus 71, a causative agent of hand, foot and mouth disease

“…Flow cytometric analyses revealed that the two representative clones that highly expressed GBA1 had lower levels of cell surface SCARB2 than their corresponding control (Figs 3 and S1), suggesting that the cell surface levels of SCARB2 were reduced by GBA1 expression. Given the transporter activity of SCARB2 [13,14], it seems likely that GBA1 overexpression may increase SCARB2 trafficking through the ER-Golgilysosome pathway, resulting in a reduction in SCARB2 targeting to the cell surface.…”

“…A mutation in SCARB2 was found to cause downregulation of GBA1 expression in epithelial cells [14], suggesting that SCARB2 may function as a molecular chaperone of GBA1. Factors that enhance EV71 infection have also been reported, including annexin II and heparin sulfate [14,15] [8,16,17]. However, intrinsic negative regulators of EV71 replication have not been documented.…”

Myoclonic Epilepsy in Lysosomal Storage Disorders

“…It was initially described in French-Canadians but it has been reported in patients with various ethnic origins (Andermann et al, 1986;Badhwar et al, 2004). It is caused by the deficiency of the lysosomal integral membrane protein type 2 (LIMP-2) (Berkovic et al, 2008, Balreira et al, 2008, an ubiquitously expressed transmembrane protein (Fujita et al , 1992) mainly found in the lysosomes and late endosomes (Fukuda, 1991), that mediates the mannose 6-phosphate-independent targeting of GBA to the lysosomes (Reczek et al, 2007). The deficient activity of LIMP-2 leads to the mistarget of the GBA protein, which can not reach the lysosome.…”

“…The deficient activity of LIMP-2 leads to the mistarget of the GBA protein, which can not reach the lysosome. In fact, this condition is characterized by pathological levels of GBA activity in fibroblasts, normal or slightly reduced levels in leukocytes, but increased levels in plasma (Balreira et al, 2008;Dardis et al, 2009). …”

“…In humans LIMP-2 is encoded by the SCARB2 gene (NM_005506) located on chromosome 4q13-21 (Reczek et al, 2007). To date, 12 mutations in the SCARB2 gene have been reported in 11 patients affected by AMRF (Berkovic et al, 2008;Balreira at al., 2008;Dardis et al, 2009;Dibbens et al, 2009). Among these mutations, five are located in intronic regions and may affect the mRNA splicing process, three are non sense, three are small deletions or insertions that cause a shift in the reading frame and one is missense.…”