Genetic basis of distal arthrogryposes

Every year millions of children are born with a birth defect. Birth defects, which can be described as abnormalities of structure or function that is present from birth, are the leading cause of infant death in developed countries and a significant cause of morbidity and economic burden in low- or middle-income countries. This dissertation addresses the genetic basis of distal arthrogryposes (DAs), a subgroup of birth defects that are characterized by contractures of the distal joints of a limb. Based on previous research of our laboratory, we hypothesized that DAs are defects of contractile apparatus in fast twitch skeletal myofibers and tested this hypothesis in four DA syndromes. We found that mutations of the embryonic myosin heavy chain gene cause DA2A and DA2B, whereas a missense mutation of the perinatal myosin heavy chain gene is responsible for DA7. Furthermore, we found mutations in the adult and extraocular myosin heavy chain genes in some DA5 patients. Furthermore, we noticed some patients with similar findings who do not meet the diagnostic criteria of the known DA syndromes. We proposed one of these conditions to be named as DA10, and mapped this condition to the long arm of chromosome 2. We named the other condition as the CATSHL syndrome, which we showed to be caused by a loss-of-function mutation in the fibroblast growth factor receptor 3 gene. The main contribution of this research is to benefit affected individuals and their families, since molecular testing can now be offered to them. In addition, through further studies leading to a better understanding of normal and abnormal development, effective strategies for prevention and treatment of congenital limb malformations can be developed.