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

• Published in: Human molecular genetics 2008-07, Vol.17 (14), p.2238-2243
• Main Authors: Balreira, Andrea, Gaspar, Paulo, Caiola, Daniel, Chaves, João, Beirão, Idalina, Lima, José Lopes, Azevedo, Jorge Eduardo, Miranda, Maria Clara Sá
• Format: Article
• Language: English
• Subjects: Adult; Base Sequence; Biological and medical sciences; Codon, Nonsense; Female; Fibroblasts - enzymology; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Glucosylceramidase - genetics; Glucosylceramidase - metabolism; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Leukocytes - enzymology; Lysosomal Membrane Proteins - genetics; Lysosomal Membrane Proteins - metabolism; Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase - metabolism; Medical sciences; Molecular and cellular biology; Myoclonic Epilepsies, Progressive - enzymology; Myoclonic Epilepsies, Progressive - genetics; Myoclonic Epilepsies, Progressive - metabolism; Nephrotic Syndrome - enzymology; Nephrotic Syndrome - genetics; Nephrotic Syndrome - metabolism; Nervous system (semeiology, syndromes); Neurology; Phenotype; Receptors, Scavenger - genetics; Receptors, Scavenger - metabolism; Skin - enzymology
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddn124

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 β-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 β-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 β-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.