Y Y Gla Domain

Fig. 3 Schematic representation of the primary amino acid sequence of the two-chain human FX. The form in circulating blood plasma lacking the tripeptide connecting the light chain to the activation peptide is shown. (From Leytus et al. Biochem. 1986, 25, 5098.)

bleeding manifestations, and homozygotes may exhibit higher than 10% activity. Thus many individuals carrying a FX mutation may remain undiagnosed or develop hemorrhagic complications only when challenged or because of an additional insult to the coagulation cascade. Although the clinical presentation of FX deficiency correlates poorly with laboratory phenotype, genetic analysis usually provides a plausible explanation for the factor X activity and antigen levels measured in the laboratory. As in other congenital coagulation disorders, FX deficiency usually arises from missense mutations. Amino acid substitutions can significantly change any number of steps in protein formation. Mutations severely impairing the protein structure are frequently associated with a reduction of the antigen as well as the activity level. In these cases, abnormal protein folding may be responsible for an impairment of protein secretion and/or a reduction in protein half-life. Missense mutations responsible for minor structural changes are often associated with an impairment in FX activity in the setting of a normal antigen level. Nonsense mutations and large gene deletions have been reported and are invariably associated with a symptomatic pattern when found in compound heterozygosis with a missense mutation impairing the FX

protein structure.[11] Interestingly, FX knockout mice with a total deficiency in blood coagulation FX present with partial embryonic lethality and fatal neonatal bleeding suggesting the crucial role of FX function.[12] It is likely that genetic mutations that cause total FX deficiency in humans may be incompatible with life as well. Very few symptomatic individuals with total or severe deficiency in the components of prothrombinase have been identified to date.

Missense mutations have been described affecting the different FX protein domains. Mutations in the preprose-quence and prosequence, as FX Nice and FX Santo Domingo, have been shown by molecular modeling and expression studies to be responsible for secretion and cleavage problems explaining the type I phenotype.[13,14]

A missense mutation affecting the calcium-binding region of the Gla domain characterize the low activity and normal antigen level in the FX St. Louis.[15]

Mutations affecting the correct formation of disulfide bridges in EGF-1 and -2 domain have been reported, affecting both the function and antigen level of FX-associated mutations.[11] Missense mutations affecting the release of the activation peptide, such as FX Wenatchee I and II, have been shown to be associated with low catalytic activity and reduced FX half-life.[16]

FX Friuli is one of the most well-characterized mutations of the catalytic domain.[17] This variant consists of a Pro343! Ser substitution within the heavy chain of FX. Homozygous FX Friuli patients present with a normal antigen level and a normal or near-normal activity by means of RVV assay but a severely reduced (4-9%) function in the intrinsic and extrinsic pathways. Due to the formation of a new hydrogen bond, the tertiary structure of the catalytic domain has been shown to be affected.

A good genotype-phenotype correlation has been demonstrated in an Italian family with FX deficiency, named FX S. Giovanni Rotondo.[18] In this well-characterized variant, one deletion in the region encoding for the activation peptide was described in compound heterozygosis with a missense mutation in the catalytic domain, respectively responsible for the lack of synthesis and/or secretion of FX and for a dysfunctional FX.

The loss of a disulfide bond in the catalytic domain has been shown to be associated with a type I phenotype in FX Padua 4.[19] Interestingly, mutations in this highly conserved residue among other serine proteases, factor VII and protein C, are responsible for a very similar phenotype, suggesting the critical role of this disulfide bond in FX function and secretion.

These few examples of a consistent genotype-pheno-type relationship further suggest that the laboratory phenotype is largely a function of the FX gene lesion segregating in the family. Some interindividual variability, even in the presence of identical pathological FX

genotypes, is common, which is likely due to the variation between laboratory assays, the contribution of polymorphisms, and possibly also the influence of variation at nonallelic loci.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

Get My Free Ebook


Post a comment