Fukutin-related protein localizes to the Golgi apparatus and mutations lead to mislocalization in muscle in vivo

Keramaris-Vrantsis, Elizabeth, Lu, Pei J., Doran, Timothy, Zillmer, Allen, Ashar, Jignya, Esapa, Christopher T., Benson, Matthew A., Blake, Derek J. ORCID: https://orcid.org/0000-0002-5005-4731, Rosenfeld, Jeffrey and Lu, Qi L. 2007. Fukutin-related protein localizes to the Golgi apparatus and mutations lead to mislocalization in muscle in vivo. Muscle & Nerve 36 (4) , pp. 455-465. 10.1002/mus.20833

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Abstract

Mutations in the fukutin-related protein gene (FKRP) are associated with a spectrum of diseases from mild limb-girdle muscular dystrophy type 2I to severe congenital muscular dystrophy type 1C, muscle–eye–brain disease (MEB), and Walker–Warburg syndrome (WWS). The effect of mutations on the transportation of the mutant proteins may constitute the underlying mechanisms for the pathogenesis of these diseases. Here we examined the subcellular localization of mouse and human normal and mutant FKRP proteins in cells and in muscle in vivo. Both normal human and mouse FKRPs localize in part of the Golgi apparatus in muscle fibers. Mutations in the FKRP gene invariably altered the localization of the protein, leading to endoplasmic reticulum retention within cells and diminished Golgi localization in muscle fibers. Our results therefore suggest that an individual missense point mutation can confer at least two independent effects on the protein, causing (1) reduction or loss of the presumed glycosyltransferase activity directly and (2) mislocalization that could further alter the function of the protein. The complexity of the effect of individual missense point mutations may partly explain the wide variation of the FKRP-related myopathies.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	fukutin, FKRP mutations, Golgi localization, muscular dystrophy
Publisher:	John Wiley & Sons
ISSN:	0148-639X
Last Modified:	24 Oct 2022 11:35
URI:	https://orca.cardiff.ac.uk/id/eprint/48650

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