In other species: rock pigeon , chicken , dog , pig , goat , sheep , rabbit , water buffalo , Japanese quail , yellow catfish

Categories: Muscle phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 601788 (gene) , 614160 (trait)

Links to MONDO diseases:

• MONDO:0013598: myostatin-related muscle hypertrophy

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1997

Cross-species summary: Abnormal increase in muscular tissue caused entirely by enlargement of existing cells (in contrast to muscular hyperplasia, in which the abnormal increase in muscular tissue is due to the formation and growth of new, normal muscle cells)

Species-specific name: Double muscling; “culón”; horse rump

Species-specific description: The double-muscle trait in cattle is characterised by an increase in muscle mass of approx 20%, resulting in substantially higher meat yield, a higher proportion of expensive cuts of meat, and lean and very tender meat, for which a substantial premium is paid. The trait is autosomal recessive, and the locus has been given the symbol mh. It occurs at such a high frequency in Piedmontese and Belgian Blue cattle that it is characteristic of these breeds. However, it also occurs in other breeds. Along with its obvious advantages, double-muscling also has one major drawback - a greatly increased incidence of calving difficulties, to the extent that Caesarian sections are the rule for deliveries within these breeds. However, its advantages are sufficient that double-muscled cattle play a major role in animal agriculture in several countries, and are found in many countries. In addition to naturally occurring variants for this trait, variants have been created artificially: Genetically-modifed organism; GMO.

History: The double-muscle trait in cattle was first described by Culley (1807).

Mapping: A genome scan using 213 mapped microsatellite markers in a Belgian Blue X Friesian backcross, conducted by Charlier et al. (1995), showed that the mh locus is at the centromeric end of chromosome 2, approximately 3.1 cM from microsatellite TCLA44. In mid 1997, McPherron et al. (1997) published the results of investigations into the gene for myostatin, a member of the transforming-growth-factor-beta-1 superfamily of peptides: mice in which the myostatin gene had been "knocked out" have a phenotype very similar to double-muscling. This immediately suggested a "candidate" gene for mh. Before long, both physical and linkage mapping had shown that myostatin maps to the mh region of bovine chromosome 2 (Grobet et al., 1997; Smith et al., 1997), making it a very likely candidate for the mh gene.

Markers: Lee et al. (2019) reported use of the p.Phe94Leu variant in genomic selection in the Limousin breed.

Molecular basis: Sequencing of myostatin DNA from homozygous normals and double-muscled cattle revealed an 11-bp deletion (of nucleotides 821 to 831), resulting in a frameshift and subsequent premature termination, in the bioactive carboxy-terminal domain of the gene in Belgian Blue cattle (Grobet et al., 1997; Kambadur et al., 1997; McPherron and Lee, 1997). This is a region that is very highly conserved in the TGF family of peptides. The same mutation is responsible for double-muscling in the Asturiana breed (Grobet et al. 1998; Georges et al., 1998). In contrast, double-muscled Piedmontese cattle have a G-A transition that changes a cysteine residue to a tyrosine in the same highly-conserved region of the gene (Kambadur et al., 1997; McPherron and Lee, 1997). In a screen of 35 double-muscled cattle from 10 European breeds, seven different sequence variants (alleles) were discovered in the coding region of the myostatin gene (Grobet et al., 1998; Georges et al., 1998). Five of these could cause a deficiency of myostatin: the 11bp deletion already described an insertion/deletion in which 10 unrelated bases are inserted in the place a 7 bases that have been deleted at nucleotide 418 a C-T transition at nucleotide 610 a G-T transversion at nucleotide 676 a G-A transition at nucleotide 938 Two other mutants were unlikely to cause a deficiency: a C-A transversion at nucleotide 282 (resulting in a conservative Phe-Leu amino-acid substitution); and a silent C-T transition at nucleotide 414. For most of the breeds, double-muscled animals were homozygous for one of the five harmful mutations, or were compound heterozygotes for two mutants. Obviously, there is considerable genetical heterogeneity in the cause of double muscling. Furthermore, the mutations are not all unique to one breed: two are shared by more than one breed. In addition, two breeds (Limousin and Blond d'Aquitane) have double-muscling but do not have any of the five harmful mutations. Clearly, there are more harmful mutations to be discovered. More importantly, the discovery that mutations in the myostatin gene have a profound effect on meat yield and quality opens the way for elucidating the role of myostatin in meat production, which in turn will suggest novel (possibly non-genetic) ways of enhancing meat yield and quality. Dierks et al. (2015) reported a novel MSTN mutation (c.191T>C, p.Leu64Pro) in double-muscled German Gelbvieh cattle.
Ren et al. (2024) “simultaneously edited three genes in bovine fibroblasts. A knockout of MSTN and PRNP was created and the amino acid Q-G in CD18 was precisely substituted [in the fibroblasts].”

Genetic engineering: Yes - in addition to the occurrence of natural variants, variants have been created artificially, e.g. by genetic engineering or gene editing
Have human generated variants been created, e.g. through genetic engineering and gene editing

Breeds: Angus (Cattle) (VBO_0000104), Asturian Valley (Cattle) (VBO_0000111), Belgian Blue (Cattle) (VBO_0000139), Blonde d'Aquitaine (Cattle) (VBO_0000151), Braford (Cattle) (VBO_0000158), Charolais (Cattle) (VBO_0000177), Gascon (Cattle) (VBO_0000209), Gelbvieh (Cattle) (VBO_0000212), Limousin (Cattle) (VBO_0000274), Maine-Anjou (Cattle) (VBO_0000286), Murray Grey (Cattle) (VBO_0000312), Parthenais (Cattle) (VBO_0000330), Piedmont (Cattle) (VBO_0000332), Santa Gertrudis (Cattle) (VBO_0000368), South Devon (Cattle) (VBO_0000385).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: