Hemophilia, Molecular Genetics of

The two X-linked hemorrhagic diseases hemophilia A and hemophilia B have made an important contribution to the understanding of human genetics. The first historical record of the inheritance of a disease and of “genetics”-motivated advice relates to these diseases, as do the first description of the X-linked pattern of inheritance, the appreciation of equilibria between selection and mutation, and the first attempt to estimate mutation rates. In modern times, the hemophilias have clearly illustrated the successes and problems of replacement therapy and have provided some insight into the causes of immunological complication associated with the therapeutic administration of the missing gene products. It is therefore not surprising that nowadays they attract the attention of scientists and clinicians involved in the development of gene therapy. The hemophilias, which affect 1/5000 males in the population, are members of a large group of diseases characterized by very high mutational heterogeneity. This group is of particular importance because, on the one hand, the wealth of natural mutants that each member possesses allows accumulation of detailed information on the structural features that are important to the functions of the gene and gene product involved in the disease; on the other, this creates the least favorable situation for the development of fully efficient strategies for the provision of the carrier and prenatal diagnoses that are necessary for genetic counseling. Surprisingly, mutation analysis in hemophilia A has revealed that homologous intranemic recombination between duplicated sequences can represent an important cause of recurring gene inactivation. Keywords: CpG and CpG island; Founder Mutation; Frameshift; Male-driven Evolution; Missense; Mutational Load; Nonsense; Uninemic; Zygote