conclude that residues 88 to 109 of the second EGF domain mediate binding to platelets and assembly of the factor X activating complex.The structures of all four domains have been solved. A structure of the two EGF domains and the trypsin-like domain was determined for the pig protein. The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR.Several structures of super active mutants have been solved, which reveal the nature of factor IX activation by other proteins in the clotting cascade. Genetics
The gene for factor IX is located on the X chromosome (Xq27.1-q27.2) and is therefore X-linked recessive: mutations in this gene affect males much more frequently than females. At least 534 disease-causing mutations in this gene have been discovered. The F9 gene was first cloned in 1982 by Kotoku Kurachi and Earl Davie.Polly, a transgenic cloned Poll Dorset sheep carrying the gene for factor IX, was produced by Dr Ian Wilmut at the Roslin Institute in 1997. Role in disease
Deficiency of factor IX causes Christmas disease (hemophilia B). Over 3000 variants of factor IX have been described, affecting 73% of the 461 residues; some cause no symptoms, but many lead to a significant bleeding disorder. The original Christmas disease mutation was identified by sequencing of Christmas DNA, revealing a mutation which changed a cysteine to a serine.Recombinant factor IX is used to treat Christmas disease.
Benign hereditary chorea (BHC), also known as benign familial chorea, is a rare autosomal dominant neurogenetic syndrome. It typically presents itself in childhood with isolated chorea, with average to below average intelligence. Unlike other neurogenetic causes of chorea such as Huntingtons disease, BHC is not progressive, and not associated with cognitive decline or psychiatric problems in the vast majority of cases.The first description of BHC was reported in 1967 in an African American family from Mississippi. Two brothers reportedly had delayed motor development in childhood and were diagnosed with chorea. These findings were reaffirmed by other families reporting similar traits and an autosomal dominant pattern of inheritance was suggested. However, heterogeneity in the presentations of the affected individuals made confirmation of these diagnoses of BHC difficult to prove. Features reported in these families, including dystonia, tremor, and myoclonus, led researchers to question whether BHC actually represents different diagnoses with similar phenotypes inappropriately grouped together.Further research in 2000 confirmed a connection between a Dutch family reporting similar characteristics of BHC and one of the original families. The investigators identified a linkage to a disease locus on the long arm of chromosome 14 from this connection. Signs and Symptoms
Benign Hereditary Chorea is characterized by early onset of an abnormal gait, speech articulation difficulties, anxiety, and chorea.The clinical spectrum of symptoms resulting from BHC is vast, manifesting as thyroid agenesis to dysarthria to distress syndrome.