Investigations on molecular aspects of Lethal Congenital Contracture Syndrome

Arthrogryposis is a clinical description of a phenotype caused by fetal immobility. More than 150 conditions presenting with congenital arthrogryposis are known. Prenatally lethal cases of arthrogryposis present a diagnostic challenge although they are more frequently encountered due to improved ultrasound methods. Post-mortem diagnostics is often hampered by fetal maseration. Therefore, accurate diagnosis is at times only descriptive and prognosis is not always possible to predict. The incidence of anterior horn cell disorders associated with arthrogryposis and early fetal demise is poorly known. Thus, more knowledge about the genetics and epidemiology of these disorders is needed. Importantly, identification of the defective pathways in these disorders would most probably expose critical elements in the normal development of human motoneurons. The Finnish Disease Heritage includes two lethal arthrogryposes. The pathogenetic mechanism of these diseases is still unknown. This thesis sheds light on the molecular mechanisms active during the pathogenesis of Lethal Congenital Contracture Syndrome. LCCS leads to death of the affected fetuses before the 32nd gestational week. The hallmark of the syndrome is degeneration of the anterior horn of the spinal cord. We localized the defective gene to chromosome 9q34.1 and provided a scaffold to sequence the genomic region. We then continued by the analysis of the positional candidate genes in the critical DNA-region, but until now the LCCS gene and the corresponding mutation remains unknown. To obtain further clues of the character of the LCCS gene and involved pathways, we performed DNA microarray experiments on LCCS spinal cords to unravel the molecular pathways that are deranged during the disease process. We observed changes in central developmental themes, including Sonic Hedgehog in addition to an indication of oligodendrocyte dysfunction. To address the implicated oligodendrocyte dysfunction further, neural precursor cells were harvested from post-mortem LCCS CNS and cultured in vitro. Neural precursor cells from both LCCS patients and age-matched controls were succesfully enriched in culture. The LCCS neural precursor cells appeared denser and assessment of proliferation indicated increased mitotic