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Impact of disease causing mutations on TMEM165 subcellular localization, a recently identified protein involved in CDG-II

Tijdschriftbijdrage - Tijdschriftartikel

TMEM165 has recently been identified as a novel protein involved in CDG-II. TMEM165 has no biological function described so far. Different mutations were recently found in patients with Golgi glycosylation defects and harboring a peculiar skeletal phenotype. In this study we examined the effect of naturally occurring mutations on the intracellular localization of TMEM165 and their abilities to complement the TMEM165 deficient yeast, gdt1Δ. Wild type TMEM165 was present within Golgi compartment, plasma membrane and late endosomes/ lysosomes while mutated TMEM165 were found differentially localized according to the mutations. We demonstrated that in the yeast functional assay with TMEM165 orthologue Gdt1, the homozygous point mutation correlating with a mild phenotype restores the yeast functional assay while the truncated mutation, associated with severe disease, failed to restore Gdt1 function. These studies highly suggest that these clinically relevant point mutations do not affect the protein function but critically changes the subcellular protein localization. Moreover, the data point to a critical role of the YNRL motif in TMEM165 subcellular localization.
Tijdschrift: Human Molecular Genetics
ISSN: 0964-6906
Issue: 14
Volume: 22
Pagina's: 2914 - 2928
Jaar van publicatie:2013