Mutations alter secretion of fukutin-related protein

Lu, Pei J., Zillmer, Allen, Wu, XiaoHua, Lochmuller, Hanns, Vachris, Judy, Blake, Derek J. ORCID: https://orcid.org/0000-0002-5005-4731, Chan, Yiumo Michael and Lu, Qi L. 2010. Mutations alter secretion of fukutin-related protein. Biochimica et Biophysica Acta - Molecular Basis of Disease 1802 (2) , pp. 253-258. 10.1016/j.bbadis.2009.10.016

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Abstract

Mutations in the fukutin-related protein (FKRP) gene cause limb-girdle muscular dystrophy type 2I (LGMD2I) as well as other severe muscle disorders, including Walker-Warburg syndrome, muscle-eye-brain disease, and congenital muscular dystrophy type 1C. The FKRP gene encodes a putative glycosyltransferase, but its precise localization and functions have yet to be determined. In the present study, we demonstrated that normal FKRP is secreted into culture medium and mutations alter the pattern of secretion in CHO cells. L276I mutation associated with mild disease phenotype was shown to reduce the level of secretion whereas P448L and C318Y mutations associated with severe disease phenotype almost abolished the secretion. However, a truncated FKRP mutant protein lacking the entire C-terminal 185 amino acids due to the E310X nonsense mutation was able to secrete as efficiently as the normal FKRP. The N-terminal signal peptide sequence is apparently cleaved from the secreted FKRP proteins. Alteration of the secretion pathway by different mutations and spontaneous read-through of nonsense mutation may contribute to wide variations in phenotypes associated with FKRP-related diseases.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Elsevier
ISSN:	0925-4439
Last Modified:	31 Oct 2022 09:31
URI:	https://orca.cardiff.ac.uk/id/eprint/81350

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