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Human Molecular Genetics Advance Access published online on April 17, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn124
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Andrea Balreira1,2, Paulo Gaspar1, Daniel Caiola1, João Chaves3, Idalina Beirão4, José Lopes Lima3, Jorge Eduardo Azevedo5,2 and Maria Clara Sá Miranda1,*

1 Unidade de Biologia do Lisossoma e do Peroxissoma (UNILIPE); Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal 2 Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal 3 Serviço de Neurologia, Hospital de S. António, Porto, Portugal 4 Serviço de Nefrologia, Hospital de S. António, Porto, Portugal 5 Biogénese e Função de Organelos (OBF), Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal

* Corresponding author: Maria Clara Sá Miranda Unidade de Biologia do Lisossoma e do Peroxissoma IBMC – Instituto de Biologia Molecular e Celular Rua do Campo Alegre, 823 4150-180 Porto Portugal Phone: 00351226074900 Fax: 00351226092404 E-mail: mcsamir{at}ibmc.up.pt

Received February 1, 2008; Revised April 13, 2008; Accepted April 13, 2008

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. 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. 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.


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