Impaired trafficking of the very low density lipoprotein receptor caused by missense mutations associated with dysequilibrium syndrome.

Dysequilibrium syndrome (DES, OMIM 224050) is a genetically heterogeneous condition that combines autosomal recessive non-progressive cerebellar ataxia with mental retardation. The subclass dysequilibrium syndrome type 1 (CAMRQ1) has been attributed to mutations in the VLDLR gene encoding the very low density lipoprotein receptor (VLDLR). This receptor is involved in the Reelin signaling pathway that guides neuronal migration in the cerebral cortex and cerebellum. Three missense mutations (c.1459G>T; p.D487Y, c.1561G>C; p.D521H and c.2117G>T; p.C706F) have been previously identified in VLDLR gene in patients with DES. However, the functional implications of those mutations are not known and therefore we undertook detailed functional analysis to elucidate the cellular mechanisms underlying their pathogenicity. The mutations have been generated by site-directed mutagenesis and then expressed in cultured cell lines. Confocal microscopy and biochemical analysis have been employed to examine the subcellular localization and functional activities of the mutated proteins relative to wild type. Our results indicate that the three missense mutations lead to defective intracellular trafficking and ER retention of the mutant VLDLR protein. This trafficking impairment prevents the mutants from reaching the plasma membrane and binding exogenous Reelin, the initiating event in Reelin signaling. Collectively, our results provide evidence that ER quality control is involved in the functional inactivation and underlying pathogenicity of these DES-associated mutations in the VLDLR.
AuthorsPraseetha Kizhakkedath, Anke Loregger, Anne John, Boris Bleijlevens, Ali S Al-Blooshi, Ahmed H Al-Hosani, Ahmed M Al-Nuaimi, Lihadh Al-Gazali, Noam Zelcer, Bassam R Ali
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1843 Issue 12 Pg. 2871-7 (Dec 2014) ISSN: 0006-3002 [Print] Netherlands
PMID25173816 (Publication Type: Journal Article)
CopyrightCopyright © 2014 Elsevier B.V. All rights reserved.

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