title: 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.
authors.affiliation: Unidade de Biologia do Lisossoma e do Peroxissoma, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Andrea
authors.initials: A
authors.lastname: Balreira
authors.forename: Paulo
authors.initials: P
authors.lastname: Gaspar
authors.forename: Daniel
authors.initials: D
authors.lastname: Caiola
authors.forename: João
authors.initials: J
authors.lastname: Chaves
authors.forename: Idalina
authors.initials: I
authors.lastname: Beirão
authors.forename: José Lopes
authors.initials: JL
authors.lastname: Lima
authors.forename: Jorge Eduardo
authors.initials: JE
authors.lastname: Azevedo
authors.forename: Maria Clara Sá
authors.initials: MC
authors.lastname: Miranda
mesh_terms: D000328:Adult; D001483:Base Sequence; D018389:Codon, Nonsense; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000201:enzymology; D051907:Lysosomal Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase / Q000378:metabolism; D020191:Myoclonic Epilepsies, Progressive / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D009404:Nephrotic Syndrome / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D051116:Receptors, Scavenger / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000201:enzymology
chemical_list: D018389:Codon, Nonsense; D051907:Lysosomal Membrane Proteins; D051116:Receptors, Scavenger; C074299:SCARB2 protein, human; D005962:Glucosylceramidase; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase