A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epi

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Hum Mol Genet. 2008 Apr 17

A nonsense mutation in the LIMP-2 gene associated with progressive

myoclonic epilepsy and nephrotic syndrome.

Balreira A, Gaspar P, Caiola D, Chaves J, Beirão I, Lopes Lima J,

Azevedo JE, Sá Miranda MC.

Unidade de Biologia do Lisossoma e do Peroxissoma (UNILIPE);

Instituto de Biologia Molecular e Celular (IBMC), Universidade do

Porto, Porto, Portugal.

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 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. 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.