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Non-synonymous FGD3 Variant as Positional Candidate for Disproportional Tall Stature Accounting for a Carcass Weight QTL (CW-3) and Skeletal Dysplasia in Japanese Black Cattle.

Takasuga A, Sato K, Nakamura R, Saito Y, Sasaki S, Tsuji T, Suzuki A, Kobayashi H, Matsuhashi T, Setoguchi K, Okabe H, Ootsubo T, Tabuchi I, Fujita T, Watanabe N, Hirano T, Nishimura S, Watanabe T, Hayakawa M, Sugimoto Y, Kojima T - PLoS Genet. (2015)

Bottom Line: The risk allele was on the same chromosome as the Q allele that increases carcass weight.Phenotypic characterization revealed that the risk allele causes disproportional tall stature and bone size that increases carcass weight in heterozygous individuals but causes disproportionately narrow chest width in homozygotes.Thus, loss of FDG3 activity may lead to subsequent loss of Cdc42 function.

View Article: PubMed Central - PubMed

Affiliation: National Livestock Breeding Center, Odakura, Nishigo, Fukushima, Japan; Shirakawa Institute of Animal Genetics, Japan Livestock Technology Association, Odakura, Nishigo, Fukushima, Japan.

ABSTRACT
Recessive skeletal dysplasia, characterized by joint- and/or hip bone-enlargement, was mapped within the critical region for a major quantitative trait locus (QTL) influencing carcass weight; previously named CW-3 in Japanese Black cattle. The risk allele was on the same chromosome as the Q allele that increases carcass weight. Phenotypic characterization revealed that the risk allele causes disproportional tall stature and bone size that increases carcass weight in heterozygous individuals but causes disproportionately narrow chest width in homozygotes. A non-synonymous variant of FGD3 was identified as a positional candidate quantitative trait nucleotide (QTN) and the corresponding mutant protein showed reduced activity as a guanine nucleotide exchange factor for Cdc42. FGD3 is expressed in the growth plate cartilage of femurs from bovine and mouse. Thus, loss of FDG3 activity may lead to subsequent loss of Cdc42 function. This would be consistent with the columnar disorganization of proliferating chondrocytes in chondrocyte-specific inactivated Cdc42 mutant mice. This is the first report showing association of FGD3 with skeletal dysplasia.

No MeSH data available.


Related in: MedlinePlus

Clinical features of skeletal dysplasia.Affected calf (A) and cow (B) are presented. Red circles show the symptoms of thin neck, extended shoulder, thick joints of the limbs, and hip bone-enlargement. (C) Tibias from cows with FGD3 Cys-171 homozygous (NLBC-1 and K) and a non-carrier control (T) cows. They were 7.1–8.3 years old. Withers height (WH), shank circumference (SC), tibia length (TL), and circumference of tibia shaft (CT) are as follows: NLBC-1, 135.6 cm (WH), 20.4 cm (SC), 38.8 cm (TL), 13.6 cm (CT); K, 140 cm (WH), 18.5 cm (SC), 38.4 cm (TL), 13.0 cm (CT); T, 128.8 cm (WH), 17.8 cm (SC), 36.6 cm (TL), 12.0 cm (CT). The arrows indicate medial malleolus and intercondylar eminence. Dashed lines were drawn to facilitate observation.
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pgen.1005433.g003: Clinical features of skeletal dysplasia.Affected calf (A) and cow (B) are presented. Red circles show the symptoms of thin neck, extended shoulder, thick joints of the limbs, and hip bone-enlargement. (C) Tibias from cows with FGD3 Cys-171 homozygous (NLBC-1 and K) and a non-carrier control (T) cows. They were 7.1–8.3 years old. Withers height (WH), shank circumference (SC), tibia length (TL), and circumference of tibia shaft (CT) are as follows: NLBC-1, 135.6 cm (WH), 20.4 cm (SC), 38.8 cm (TL), 13.6 cm (CT); K, 140 cm (WH), 18.5 cm (SC), 38.4 cm (TL), 13.0 cm (CT); T, 128.8 cm (WH), 17.8 cm (SC), 36.6 cm (TL), 12.0 cm (CT). The arrows indicate medial malleolus and intercondylar eminence. Dashed lines were drawn to facilitate observation.

Mentions: Skeletal dysplasia, characterized by joint- and/or hip bone-enlargement, has been known in a specific lineage of Japanese Black cattle (Fig 3A and 3B). The disease causes economic damage to farmers because affected animals are bony and not fattened well. Since affected animals were produced from Sire II and its related sires, P and Q (Fig 1A), 14 affected and 34 control animals from the three families were genotyped with the BovineSNP50 Genotyping BeadChip. Genotypes were used for homozygosity and autozygosity mapping using ASSHOM and ASSIST programs, respectively [14]. Both programs showed genome-wide significant signals on BTA8 (p = < 10–4) (Fig 4A), and the plot of p-values on BTA8 (Fig 4B) was similar to that of the GWAS for carcass weight [7] (Fig 2). The risk haplotype was on the same chromosome as the CW-3 Q haplotype in Sire II. Another 22 affected animals were collected from various sires and genotyped with BovineSNP50. Of 36 affected animals, 29 (80.6%) shared a homozygous 2.36-Mb risk haplotype between ARS-BFGL-NGS-108358 (84.18 Mb) and BTA-52694-no-rs (86.54 Mb) (Fig 4C). Of the remaining seven affected animals, two did not possess the risk haplotype and five were heterozygous along BTA8. The initial mapping contained three of the seven animals, while no significant regions were detected when the 7 affected and 34 control animals were subjected to ASSHOM (p > 0.7) and ASSIST programs (p > 0.11). These seven animals may be erroneously diagnosed, because the disease phenotype is highly variable and the conditions are quantitative rather than qualitative as described below (Fig 5B and S2 Table).


Non-synonymous FGD3 Variant as Positional Candidate for Disproportional Tall Stature Accounting for a Carcass Weight QTL (CW-3) and Skeletal Dysplasia in Japanese Black Cattle.

Takasuga A, Sato K, Nakamura R, Saito Y, Sasaki S, Tsuji T, Suzuki A, Kobayashi H, Matsuhashi T, Setoguchi K, Okabe H, Ootsubo T, Tabuchi I, Fujita T, Watanabe N, Hirano T, Nishimura S, Watanabe T, Hayakawa M, Sugimoto Y, Kojima T - PLoS Genet. (2015)

Clinical features of skeletal dysplasia.Affected calf (A) and cow (B) are presented. Red circles show the symptoms of thin neck, extended shoulder, thick joints of the limbs, and hip bone-enlargement. (C) Tibias from cows with FGD3 Cys-171 homozygous (NLBC-1 and K) and a non-carrier control (T) cows. They were 7.1–8.3 years old. Withers height (WH), shank circumference (SC), tibia length (TL), and circumference of tibia shaft (CT) are as follows: NLBC-1, 135.6 cm (WH), 20.4 cm (SC), 38.8 cm (TL), 13.6 cm (CT); K, 140 cm (WH), 18.5 cm (SC), 38.4 cm (TL), 13.0 cm (CT); T, 128.8 cm (WH), 17.8 cm (SC), 36.6 cm (TL), 12.0 cm (CT). The arrows indicate medial malleolus and intercondylar eminence. Dashed lines were drawn to facilitate observation.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4549114&req=5

pgen.1005433.g003: Clinical features of skeletal dysplasia.Affected calf (A) and cow (B) are presented. Red circles show the symptoms of thin neck, extended shoulder, thick joints of the limbs, and hip bone-enlargement. (C) Tibias from cows with FGD3 Cys-171 homozygous (NLBC-1 and K) and a non-carrier control (T) cows. They were 7.1–8.3 years old. Withers height (WH), shank circumference (SC), tibia length (TL), and circumference of tibia shaft (CT) are as follows: NLBC-1, 135.6 cm (WH), 20.4 cm (SC), 38.8 cm (TL), 13.6 cm (CT); K, 140 cm (WH), 18.5 cm (SC), 38.4 cm (TL), 13.0 cm (CT); T, 128.8 cm (WH), 17.8 cm (SC), 36.6 cm (TL), 12.0 cm (CT). The arrows indicate medial malleolus and intercondylar eminence. Dashed lines were drawn to facilitate observation.
Mentions: Skeletal dysplasia, characterized by joint- and/or hip bone-enlargement, has been known in a specific lineage of Japanese Black cattle (Fig 3A and 3B). The disease causes economic damage to farmers because affected animals are bony and not fattened well. Since affected animals were produced from Sire II and its related sires, P and Q (Fig 1A), 14 affected and 34 control animals from the three families were genotyped with the BovineSNP50 Genotyping BeadChip. Genotypes were used for homozygosity and autozygosity mapping using ASSHOM and ASSIST programs, respectively [14]. Both programs showed genome-wide significant signals on BTA8 (p = < 10–4) (Fig 4A), and the plot of p-values on BTA8 (Fig 4B) was similar to that of the GWAS for carcass weight [7] (Fig 2). The risk haplotype was on the same chromosome as the CW-3 Q haplotype in Sire II. Another 22 affected animals were collected from various sires and genotyped with BovineSNP50. Of 36 affected animals, 29 (80.6%) shared a homozygous 2.36-Mb risk haplotype between ARS-BFGL-NGS-108358 (84.18 Mb) and BTA-52694-no-rs (86.54 Mb) (Fig 4C). Of the remaining seven affected animals, two did not possess the risk haplotype and five were heterozygous along BTA8. The initial mapping contained three of the seven animals, while no significant regions were detected when the 7 affected and 34 control animals were subjected to ASSHOM (p > 0.7) and ASSIST programs (p > 0.11). These seven animals may be erroneously diagnosed, because the disease phenotype is highly variable and the conditions are quantitative rather than qualitative as described below (Fig 5B and S2 Table).

Bottom Line: The risk allele was on the same chromosome as the Q allele that increases carcass weight.Phenotypic characterization revealed that the risk allele causes disproportional tall stature and bone size that increases carcass weight in heterozygous individuals but causes disproportionately narrow chest width in homozygotes.Thus, loss of FDG3 activity may lead to subsequent loss of Cdc42 function.

View Article: PubMed Central - PubMed

Affiliation: National Livestock Breeding Center, Odakura, Nishigo, Fukushima, Japan; Shirakawa Institute of Animal Genetics, Japan Livestock Technology Association, Odakura, Nishigo, Fukushima, Japan.

ABSTRACT
Recessive skeletal dysplasia, characterized by joint- and/or hip bone-enlargement, was mapped within the critical region for a major quantitative trait locus (QTL) influencing carcass weight; previously named CW-3 in Japanese Black cattle. The risk allele was on the same chromosome as the Q allele that increases carcass weight. Phenotypic characterization revealed that the risk allele causes disproportional tall stature and bone size that increases carcass weight in heterozygous individuals but causes disproportionately narrow chest width in homozygotes. A non-synonymous variant of FGD3 was identified as a positional candidate quantitative trait nucleotide (QTN) and the corresponding mutant protein showed reduced activity as a guanine nucleotide exchange factor for Cdc42. FGD3 is expressed in the growth plate cartilage of femurs from bovine and mouse. Thus, loss of FDG3 activity may lead to subsequent loss of Cdc42 function. This would be consistent with the columnar disorganization of proliferating chondrocytes in chondrocyte-specific inactivated Cdc42 mutant mice. This is the first report showing association of FGD3 with skeletal dysplasia.

No MeSH data available.


Related in: MedlinePlus