Abstract for presentation at 11th International Congress of Human Genetics

Skeletal development and linear growth is mediated by endochondral ossification (EO), a highly coordinated programme of chondrocyte differentiation, proliferation, maturation and hypertrophy and replacement of cartilage by bone. This programme is controlled by proper synthesis and compartmentalization of matrix molecules within the growth plate and a complex network of regulatory molecules and cell-matrix interactions.
I will illustrate how the genetic analyses of mutant mouse models have contributed to a better understanding of how mutations in key genes and pathways perturb skeletal patterning and development.
We have studied the in vivo impact on EO, of expressing mutant proteins (collagens II and X, aggrecan) which result in misfolding and impaired secretion. We provide insight into a novel mechanism by which chondrocytes alleviate and survive endoplasmic reticulum stress induced by misfolded proteins.
Brachydactyly type A1 is an autosomal dominant disorder characterized by shortening or absence of the middle phalanx of digits. We have created a BDA-1 mouse model with a human equivalent of an amino acid substitution mutation (E95K) in Indian hedgehog. Analyses of these mice provide insight into how changes in the efficiency and range of Ihh signaling affect digit patterning and formation.
Mutations in the human gene, SOX9, are associated with the skeletal malformation syndrome, campomelic dysplasia (CD) and sex reversal. Complete inactivation of the Sox9 gene in mice results in failure of cartilage formation, presumably because of failure to express SOX9 target genes such as Col2a1, Col9a1, Col11a2. We have generated mice bearing a conditional Campomelic Dysplasia mutation in Sox9, an Y440X nonsense mutation causing premature termination within the trans-activation domain of SOX9 (Sox9Y440X). The impact of expressing the Sox9 CD mutation specifically in the developing notochord on development of the axial skeleton will be described.