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Phenotypic Spectrum of ?-Dystroglycanopathies Associated With the c.919T>a Variant in the FKRP Gene in Humans and Mice

Brown, S C; Fernandez-Fuente, M; Muntoni, F; Vissing, J


S C Brown

M Fernandez-Fuente

F Muntoni

J Vissing


Abstract Mutations in the fukutin-related protein gene, FKRP, are the most frequent single cause of ?-dystroglycanopathy. Rare FKRP mutations are clinically not well characterized. Here, we review the phenotype associated with the rare c.919T>A mutation in FKRP in humans and mice. We describe clinical and paraclinical findings in 6 patients, 2 homozygous, and 4-compound heterozygous for c.919T>A, and compare findings with a mouse model we generated, which is homozygous for the same mutation. In patients, the mutation at the homozygous state is associated with a severe congenital muscular dystrophy phenotype invariably characterized by severe multisystem disease and early death. Compound heterozygous patients have a severe limb-girdle muscular dystrophy phenotype, loss of ambulation before age 20 and respiratory insufficiency. In contrast, mice homozygous for the same mutation show no symptoms or signs of muscle disease. Evidence therefore defines the FKRP c.919T>A as a very severe mutation in humans. The huge discrepancy between phenotypes in humans and mice suggests that differences in protein folding/processing exist between human and mouse Fkrp. This emphasizes the need for more detailed structural analyses of FKRP and shows the challenges of developing appropriate animal models of dystroglycanopathies that mimic the disease course in humans.


Brown, S. C., Fernandez-Fuente, M., Muntoni, F., & Vissing, J. (2020). Phenotypic Spectrum of ?-Dystroglycanopathies Associated With the c.919T>a Variant in the FKRP Gene in Humans and Mice. Journal of Neuropathology and Experimental Neurology,

Journal Article Type Article
Acceptance Date Oct 13, 2020
Publication Date Oct 14, 2020
Deposit Date Oct 28, 2020
Journal Journal of Neuropathology & Experimental Neurology
Print ISSN 0022-3069
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Keywords Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Neurology, Clinical Neurology, General Medicine
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