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Fukutin‐related protein localizes to the Golgi apparatus and mutations lead to mislocalization in muscle in vivo
Author(s) -
KeramarisVrantsis Elizabeth,
Lu Pei J.,
Doran Timothy,
Zillmer Allen,
Ashar Jignya,
Esapa Christopher T.,
Benson Matthew A.,
Blake Derek J.,
Rosenfeld Jeffrey,
Lu Qi L.
Publication year - 2007
Publication title -
muscle and nerve
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.025
H-Index - 145
eISSN - 1097-4598
pISSN - 0148-639X
DOI - 10.1002/mus.20833
Subject(s) - limb girdle muscular dystrophy , endoplasmic reticulum , muscular dystrophy , golgi apparatus , biology , missense mutation , microbiology and biotechnology , mutant , mutant protein , mutation , congenital muscular dystrophy , muscle disorder , gene , genetics , medicine
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. Muscle Nerve, 2007