7/14/2023 0 Comments Tetra amelia![]() Expression of the sonic hedgehog ( Shh) gene produces a polarizing signal and controls anterior/posterior patterning, whereas Wnt signalling controls dorsal/ventral patterning. Outgrowth is promoted by a fibroblast growth factor (FGF) signal allowing proximal/distal patterning. The genetic regulation of limb development is conserved across species and governed by a three-dimensional signalling system that defines proximodistal, anteroposterior and dorsoventral axes. Similar defects have been described only in humans and chickens (Table 1). Tetradysmelia, which is characterized by a severe reduction of all limb parts distal of the scapula and the pelvic girdle, is an extremely rare limb malformation in cattle. Since signalling pathways involved in limb development are conserved across species, the observed inherited defect may serve as a model to further elucidate fundamental pathways of limb development. To our knowledge, this is the first reported candidate causal mutation for tetradysmelia in a large animal model. ![]() We identified a 50-kb deletion on BTA14 that disrupts the coding sequence of the RSPO2 gene and is associated with bovine tetradysmelia. R-spondin 2 is a secreted ligand of leucine-rich repeats containing G protein-coupled receptors that enhance Wnt signalling and is involved in a broad range of developmental processes during embryogenesis. The deletion spanned three exons of the bovine R-spondin 2 ( RSPO2) gene, which encode three domains of the respective protein. Using PCR, we confirmed that this detected deletion segregated perfectly within the family with tetradysmelia. ![]() Therefore, we subsequently performed a more comprehensive analysis by also considering structural variants and detected a 50-kb deletion in the targeted chromosomal region that was in the heterozygous state in the cases’ sire. We sequenced the whole genome of the cases’ sire and searched for heterozygous single nucleotide polymorphisms (SNPs) and small variants on BTA14 that were uniquely present in the sire and absent from 3102 control whole-genome sequences of the 1000 Bull Genomes Project, but none were identified in the 10.54-Mb candidate region on BTA14. Only calves that were diagnosed with tetradysmelia shared a distinct homozygous haplotype for this region. Applying a homozygosity mapping approach, we identified a homozygous region of 10.54 Mb on chromosome 14 ( Bos taurus BTA14). Pathological examination of four tetradysmelia cases revealed a uniform and severe dysmelia of all limbs. In order to identify the genetic basis of the disorder, we genotyped three affected calves, five dams and nine unaffected siblings using a Bovine Illumina 50 k BeadChip and sequenced the whole genome of the sire. We studied a Holstein Friesian backcross family with 24 offspring, among which six calves displayed autosomal recessive tetradysmelia. Tetradysmelia is a rare genetic disorder that is characterized by an extremely severe reduction of all limb parts distal of the scapula and pelvic girdle.
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