RGD Reference Report - Post-Natal knockdown of fukutin-related protein expression in muscle by long-termRNA interference induces dystrophic pathology [corrected]. - Rat Genome Database

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Post-Natal knockdown of fukutin-related protein expression in muscle by long-termRNA interference induces dystrophic pathology [corrected].

Authors: Wang, Chi-Hsien  Chan, Yiumo Michael  Tang, Ru-Hang  Xiao, Bin  Lu, Peijuan  Keramaris-Vrantsis, Elizabeth  Zheng, Hui  Qiao, Chunping  Jiang, Jiangang  Li, Juan  Ma, Hsin-I  Lu, Qilong  Xiao, Xiao 
Citation: Wang CH, etal., Am J Pathol. 2011 Jan;178(1):261-72. doi: 10.1016/j.ajpath.2010.11.020. Epub 2010 Dec 23.
RGD ID: 11667970
Pubmed: PMID:21224063   (View Abstract at PubMed)
PMCID: PMC3069925   (View Article at PubMed Central)
DOI: DOI:10.1016/j.ajpath.2010.11.020   (Journal Full-text)

Limb-girdle muscular dystrophy 2I (LGMD2I) is caused by mutations in the fukutin-related protein (FKRP) gene. Unlike its severe allelic forms, LGMD2I usually involves slower onset and milder course without defects in the central nervous system. The lack of viable animal models that closely recapitulate LGMD2I clinical phenotypes led us to use RNA interference technology to knock down FKRP expression via postnatal gene delivery so as to circumvent embryonic lethality. Specifically, an adeno-associated viral vector was used to deliver short hairpin (shRNA) genes to healthy ICR mice. Adeno-associated viral vectors expressing a single shRNA or two different shRNAs were injected one time into the hind limb muscles. We showed that FKRP expression at 10 months postinjection was reduced by about 50% with a single shRNA and by 75% with the dual shRNA cassette. Dual-cassette injection also reduced a-dystroglycan glycosylation and its affinity to laminin by up to 70% and induced α-dystrophic pathology, including fibrosis and central nucleation, in more than 50% of the myofibers at 10 months after injection. These results suggest that the reduction of approximately or more than 75% of the normal level of FKRP expression induces chronic dystrophic phenotypes in skeletal muscles. Furthermore, the restoration of about 25% of the normal FKRP level could be sufficient for LGMD2I therapy to correct the genetic deficiency effectively and prevent dystrophic pathology.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Muscular Dystrophy, Animal  ISOFkrp (Mus musculus)11667970; 11667970 RGD 
Muscular Dystrophy, Animal  IMP 11667970 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Fkrp  (fukutin related protein)

Genes (Mus musculus)
Fkrp  (fukutin related protein)

Genes (Homo sapiens)
FKRP  (fukutin related protein)


Additional Information