A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep

Clop, Alex; Marcq, Fabienne; Takeda, Hitoshi; Pirottin, Dimitri; Tordoir, Xavier; Bibé, Bernard; Bouix, Jacques; Caiment, Florian; Elsen, Jean-Michel; Eychenne, Francis; Larzul, Catherine; Laville, Élisabeth; Meish, Françoise; Milenković, Dragan; Tobin, James F.; Charlier, Carole; Georges, Michel

doi:10.1038/ng1810

Cited by 1,152 publications

(917 citation statements)

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“…1 However, the focus is principally on finding genetic association with common SNPs located in miR genes or miR-binding target sites, 2 and very few studies aimed to identify rarer variants in case-control series even if large scale resequencing approaches focusing on miR genes and 3ʹ-UTR are starting to be used. 3 This paucity of mutation screening studies could stem from the difficulty in interpreting rare variants that would be identified by such an approach, miR true targets remaining rather scarce, their genes poorly characterized, not to mention their regulation.…”

Section: Introductionmentioning

confidence: 99%

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

et al. 2016

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Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3ʹ-untranslated regions (3ʹ-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1-and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3ʹ-UTR and one in BRCA2 3ʹ-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3ʹ-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3ʹ-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.

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Section: Introductionmentioning

confidence: 99%

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

et al. 2016

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“…Deletions or mutations in the GDF8 gene can cause an increase in skeletal muscle mass as a result of both muscle hypertrophy and hyperplasia in a number of animal species including sheep (Clop et al, 2006), cattle (Gill et al, 2009;Kambadur et al, 1997) and dog (Mosher et al, 2007). GDF11 also appears to play a crucial role in skeletal development, as knock-out mice display skeletal defects resulting from abnormal anterior-posterior patterning (McPherron et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Variation in the ovine WFIKKN2 gene

Wang

Zhou

Qian

et al. 2014

Gene

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a b s t r a c t a r t i c l e i n f oWFIKKN2 may play a role in the regulation of muscle growth and development through its interaction with growth and differentiation factor 8 (GDF8) and growth and differentiation factor 11 (GDF11), but to date research into the function of the protein has been focused on mice, even though the WFIKKN2 gene (WFIKKN2) was first identified in humans in 2001. In this study two regions (intron 1 and the 3′ UTR) of ovine WFIKKN2 were investigated, using Polymerase Chain Reaction-Single Stranded Conformational Polymorphism (PCR-SSCP). Two different PCR-SSCP patterns, representing two unique DNA sequences (designated a and b) were detected in a 399-bp amplicon derived from the 3′ UTR, with sequence analysis revealing one single nucleotide polymorphism (SNP). In a 421-bp amplicon from intron 1, five different PCR-SSCP patterns (designated A-E) were observed and twelve SNPs were detected. Either one or two different sequences were detected in individual sheep and all the sequences identified shared homology with the WFIKKN2 sequences from cattle and other animal species, suggesting that these sequences represent variants of the ovine WFIKKN2 gene. In intron 1 of 487 sheep from eight breeds, variants B and C were the most common, followed by A, D and E. These results indicate that ovine WFIKKN2 is polymorphic and suggest that further analysis is required to see if variation in the gene is associated with variation in growth and muscle traits in sheep.

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“…In Texel sheep, the myostatin allele characterized by a G to A mutation in myostatin 3'UTR creates a target site for miR-1 and miR-206 (Clop et al, 2006). High expression of miR-1/ 206 in muscle inhibits transcript level of myostatin, which contributes to muscular hypertrophy (Clop et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-27a promotes porcine myoblast proliferation by downregulating myostatin expression

Yang

Chen

Huang

et al. 2014

Animal

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MicroRNAs are endogenous~22nt RNAs that negatively regulate gene expression at the posttranscriptional level via binding to the 3′-untranslated region (3′UTR) of target mRNAs. The microRNA miR-27a was reported to depress the expression of myostatin, a critical inhibitor of skeletal myogenesis, by binding to its 3′UTR in mouse. In this study, we cloned the full-length 3′UTR of porcine myostatin by rapid amplification of 3′-cDNA ends (3′-RACE) and demonstrated that the 3′UTR of porcine myostatin is targeted by miR-27a. The phenomenon that the level of myostatin inversely correlated with miR-27a was observed in fat and heart of pigs and also in proliferating porcine myoblasts. Besides, overexpression of miR-27a in porcine myoblasts promoted cell proliferation by reducing the expression of myostatin. Our data suggest that miR-27a positive regulates porcine myoblast proliferation via targeting myostatin.

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A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep

Cited by 1,152 publications

References 18 publications

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

Variation in the ovine WFIKKN2 gene

MicroRNA-27a promotes porcine myoblast proliferation by downregulating myostatin expression

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