The main purpose of the studies described in this thesis is to find the genetic deficit in Ollier disease and Maffucci syndrome. They are very rare, non-inherited syndromes with a unilateral... Show moreThe main purpose of the studies described in this thesis is to find the genetic deficit in Ollier disease and Maffucci syndrome. They are very rare, non-inherited syndromes with a unilateral predominance of the multiple enchondromas. Enchondroma is a benign cartilage forming tumor which can undergo malignant transformation towards chondrosarcoma. We hypothesized the presence of somatic mosaicism with an early post zygotic mutation. We used genome-wide and hypothesis driven approach to identify genes causing Ollier disease and Maffucci syndrome. Ultimately, we identified mutations in two genes (IDH1 and IDH2) that were present in the majority of the tumors from patients with Ollier disease and Maffucci syndrome. A subgroup of patients did not show mutations in IDH1, IDH2 or PTH1R and therefore, other genes (except ACP5, PTPN11, PTHLH, GNAS, NDST1) might be involved. Moreover, one can not exclude the possibility of functional links or pathways shared between IDH1 or IDH2 with EXT1, EXT2, PTH1R, PTPN11, PTHLH, TET2 and ACP5. We have shown that IDH1 mutations are associated with hypermethylation and consequently downregulation of several genes. DLX5 was the most differentially methylated gene between enchondromas with, and without IDH1 mutations which was found in our study. Show less
Osteoarthritis (OA) is a prevalent and complex disorder with a high hereditary probability. Previous genetic research into OA has yielded several common gene variants contributing to joint... Show moreOsteoarthritis (OA) is a prevalent and complex disorder with a high hereditary probability. Previous genetic research into OA has yielded several common gene variants contributing to joint specific OA phenotypes. Only a few studies allowed an examination of multiple joint sites in the patients included. In this thesis, we have focused, on the identification and investigation of OA susceptibility of rare and common generalised OA (GOA) in family based studies and common OA in the population. We investigated previously reported relationships between two candidate genes (FRZB and MATN3) with OA in a random sample from the population-based Rotterdam study and in siblings from the Genetics Osteoarthritis and Progression (GARP) study. A functional variant in FRZB indeed associates to OA but this seems not confined to hip only. Associations of MATN3 variants suggest that genetic variation in this gene determines susceptibility to spinal disc degeneration and OA of the first carpometacarpal joint. Different linkage areas were identified for early and late onset GOA. We mapped a major locus for OA at multiple joint sites on 14q32.11 in middle aged siblings from the GARP study and on 2q33.3 in seven early onset families. From our studies so far, DIO2, IDH1 and NRP2 may be new OA loci. Show less
