Human Molecular Genetics Advance Access originally published online on April 17, 2008
Human Molecular Genetics 2008 17(14):2238-2243; doi:10.1093/hmg/ddn124
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A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome
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 Biogénese e Funcão de Organelos, Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal 4 Serviço de Neurologia 5 Serviço de Nefrologia, Hospital de S. António, Porto, Portugal
* To whom correspondence should be addressed at: Unidade de Biologia do Lisossoma e do Peroxissoma, IBMC—Instituto de Biologia Molecular e Celular, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal. Tel: +351 226074900; Fax: +351 226074969; Email: mcsamir{at}ibmc.up.pt
Received February 1, 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. 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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