RESUMEN
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.
Asunto(s)
Enfermedades del Desarrollo Óseo/veterinaria , Enfermedades de los Bovinos/genética , Factores de Intercambio de Guanina Nucleótido/genética , Secuencia de Aminoácidos , Animales , Estatura/genética , Peso Corporal/genética , Enfermedades del Desarrollo Óseo/genética , Bovinos , Análisis Mutacional de ADN , Femenino , Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Placa de Crecimiento/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Haplotipos , Homocigoto , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Datos de Secuencia Molecular , Mutación Missense , Linaje , Proteínas Tirosina Fosfatasas/genética , Sitios de Carácter Cuantitativo , RiesgoRESUMEN
We have focused attention on functions of Drosophila damaged DNA binding protein 1 (D-DDB1) in Drosophila hematopoiesis and previously reported that its whole body dsRNA over-expression using a GAL4-UAS targeted expression system results in melanotic tumors and complete lethality. Since the lesions appear to arise as a normal and heritable response to abnormal development, forming groups of cells that are recognized by the immune system and encapsulated in melanized cuticle, D-DDB1 appears to be an essential development-associated factor in Drosophila. To probe the possibility that it contributes to hemocyte development, we used a collagen promoter-GAL4 strain to over-express dsRNA of D-DDB1 in Drosophila hemocytes. The D-DDB1 gene silencing caused melanotic tumors and mortality at the end of larval development. Similarly, it interfered with melanization and synthesis of antimicrobial peptides. Transgenic flies with D-DDB1 gene silencing were found to accumulate abnormal large blood cells, reminiscent of human leukemia, suggesting that D-DDB1 has functions in hemocyte development.
