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      Mutations inmyostatin(GDF8) in Double-Muscled Belgian Blue and Piedmontese Cattle

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      Genome Research

      Cold Spring Harbor Laboratory

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          Abstract

          A visibly distinct muscular hypertrophy (mh), commonly known as double muscling, occurs with high frequency in the Belgian Blue and Piedmontese cattle breeds. The autosomal recessive mh locus causing double-muscling condition in these cattle maps to bovine chromosome 2 within the same interval as myostatin, a member of the TGF-beta superfamily of genes. Because targeted disruption of myostatin in mice results in a muscular phenotype very similar to that seen in double-muscled cattle, we have evaluated this gene as a candidate gene for double-muscling condition by cloning the bovine myostatin cDNA and examining the expression pattern and sequence of the gene in normal and double-muscled cattle. The analysis demonstrates that the levels and timing of expression do not appear to differ between Belgian Blue and normal animals, as both classes show expression initiating during fetal development and being maintained in adult muscle. Moreover, sequence analysis reveals mutations in heavy-muscled cattle of both breeds. Belgian Blue cattle are homozygous for an 11-bp deletion in the coding region that is not detected in cDNA of any normal animals examined. This deletion results in a frame-shift mutation that removes the portion of the Myostatin protein that is most highly conserved among TGF-beta family members and that is the portion targeted for disruption in the mouse study. Piedmontese animals tested have a G-A transition in the same region that changes a cysteine residue to a tyrosine. This mutation alters one of the residues that are hallmarks of the TGF-beta family and are highly conserved during evolution and among members of the gene family. It therefore appears likely that the mh allele in these breeds involves mutation within the myostatin gene and that myostatin is a negative regulator of muscle growth in cattle as well as mice.

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          Dystrophin deficiency causes lethal muscle hypertrophy in cats.

          Two 5-month-old male Domestic Shorthair littermates showed general skeletal muscle hypertrophy, multifocal submucosal lingual calcification with lingual enlargement, and excessive salivation. Both cats had a reduced level of activity, walked with a stiff gait, and tended to "bunny hop" when they ran. These clinical features were similar to those of previously reported dystrophin-deficient cats. Using multiple dystrophin antibodies, we found that the cats described in this report also showed marked dystrophin deficiency. The histopathology was remarkable for hypertrophy and splitting of fibers, and progressive accumulation of calcium deposits within the muscle. There was little or no endomysial fibrosis at 2 years of age. The natural history of dystrophin-deficiency in cats has not been described: both previous cats had been euthanized at 2 years of age prior to experiencing any life-threatening problems. At 6 months of age, one of the new cats developed megaesophagus because of severe progressive hypertrophy of the diaphragmatic muscles. The diaphragm completely occluded the esophagus, and the cat was euthanized for humane reasons. The second cat remained in good condition until age 18 months when it developed acute renal failure attributed to severe prolonged dehydration and hyperosmolality. The cat recovered after receiving supportive treatment but was unable to maintain fluid homeostasis. The insufficient water intake was attributed to glossal hypertrophy and dysfunction. At age 2 years, the cat received regular subcutaneous injections of low-sodium fluids to maintain proper hydration. The clinical consequence of dystrophin deficiency in cats is lethal muscle hypertrophy. We have called the feline disease "hypertrophic feline muscular dystrophy" (HFMD).
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            The mh gene causing double-muscling in cattle maps to bovine Chromosome 2.

            While the hereditary nature of the "double-muscling" phenotype (a generalized muscular hypertrophy documented in several cattle breeds) is well established, its precise segregation mode has remained controversial. Both monogenic models (autosomal dominant or recessive) and oligogenic models have been proposed. Using a panel of 213 bovine microsatellite markers, and an experimental pedigree obtained by backing "double-muscled (Belgian Blue) x conventional (Friesian)"1 dams to double-muscle sire, we have mapped a locus on bovine Chromosome (CHr) 2 that accounts for all the phenotypic variance in the backcross generation. This locus, referred to as mh (muscular hypertrophy), has been positioned with respects to a map composed of seven Chr 2-specific microsatellites, at 2 cM from the closet marker. This result confirms the validity in the Belgian Blue population of the monogenic model involving an autosomal mh locus, characterized by a wild-type "+" and a recessive "mh" allele, causing the double-muscling phenotype in the homozygous condition. The linkage relationship between the mh locus and the Chr 2 markers was confirmed in three informative pedigrees collected from the general Belgian Blue Cattle population, reinforcing the notice of genetic homogeneity of the double-muscling trait in this breed. This work paves the way towards marker-assisted selection for or against the double muscling trait, and towards positional cloning of the corresponding gene.
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              Association of the muscle hypertrophy locus with carcass traits in beef cattle.

              A locus near the centromere of bovine chromosome 2 is responsible for muscle hypertrophy (mh) in cattle. The objectives of this study were to refine the genomic region in which the locus resides and to assess the effects of a single copy of the mh allele on carcass and birth traits. Two half-sib families were developed using a Belgian Blue x MARC III (n = 246) or a Piedmontese x Angus (n = 209) sire. Traits analyzed were calving ease (CE), birth weight (BWT, kg), longissimus rib eye area (REA), retail product yield (RPYD), USDA yield grade (YG), marbling (MAR), fat thickness (FAT), estimated kidney, pelvic, and heart fat (KPH), and longissimus tenderness measured as Warner-Bratzler shear force at 3 (S3) and 14 (S14) d postmortem. Six microsatellites were used to determine the presence or absence of the mh allele and to confirm the location of the locus affecting the traits, which was assessed to be 4 cM from the beginning of the linkage group, with the 95% confidence interval between 2 and 6 cM. Cattle with an mh allele had increased (P .10) for CE, S3, and S14. Allelic differences due to the mh locus were similar for both sources (Belgian Blue or Piedmontese). Individuals inheriting a single mh allele had a leaner, more heavily muscled carcass compared with those inheriting the alternative allele. Thus, mating schemes that maximize production of mh/+ genotypes provide a viable approach for improving carcass composition.
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                Author and article information

                Journal
                Genome Research
                Genome Res.
                Cold Spring Harbor Laboratory
                1088-9051
                1549-5469
                September 01 1997
                September 01 1997
                September 01 1997
                : 7
                : 9
                : 910-915
                Article
                10.1101/gr.7.9.910
                9314496
                © 1997

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