Nine independentF9 mutations in the Mexican hemophilia B population: Nonrandom recurrences of point mutation events in the human germline

Abstract

The factor IX gene (F9) is a valuable model for studying germ-line mutations. Nine mutations were detected in nine Mexican patients with hemophilia B by direct sequencing using genomic amplification with transcript sequencing (GAWTS): six single base changes, one micro-deletion, and two large deletions. Germline origins of mutations were found in three of six families with sporadic cases. Curiously, the four independent single base substitutions which were not at CpG dinucleotides occurred at only two different nucleotide positions (17,678 and 17,747) one transition and one transversion at each. The two remaining substitutions were identical changes at a CpG dinucleotide, but were determined to be independent by germline origin analysis. A statistical analysis suggests that the independent recurrence of mutations at these locations may reflect an unusual aspect of F9 mutagenesis in the Mexican population. These data raise the possibility of population-specific differences in human germline mutations.

Molecular pathology of haemophilia A in Turkish patients: identification of 36 independent mutations

“…It is possible that the existence of only one large deletion may represent a characteristic feature for the Turkish population. Such differences between different populations have already been observed [22,23].…”

Genotype-Phenotype Interaction Analyses in Hemophilia

“…From a study of nine independent Mexican hemophilia B families (Jaloma-Cruz et al, 2000), we found a particular mechanism of recurrent mutagenesis by four single independent substitutions in two similar non-CpG sites at nucleotide positions 17,678 (C88Y, C88F) and 17,747 (C111S, C111Y) of factor IX gene (Table 1). Using a statistical test considering a mutation target of 439 nucleotide position non-CpG sites in the coding region of factor IX (where >96% of factor IX gene mutations occur), it was demonstrated that the observed mutations were nonrandom events (p = 0.0004) (Jaloma-Cruz et al, 2000).…”

“…Using a statistical test considering a mutation target of 439 nucleotide position non-CpG sites in the coding region of factor IX (where >96% of factor IX gene mutations occur), it was demonstrated that the observed mutations were nonrandom events (p = 0.0004) (Jaloma-Cruz et al, 2000). These mutations were considered as first-line evidence of a mechanism of recurrent mutation in hemophilia involving unusual hot-spot sites.…”

“…HB762: the mother was a carrier, but the sequence change at 20,519 was not present in 13 maternal aunts and uncles or in the maternal grandfather. Jaloma et al, 2000) 2.4 Genotype-phenotype correlation in hemophilia As with monogenic diseases, hemophilia A and B have a direct relationship between factor VIII and factor IX gene mutations, respectively, and their causative phenotype effect at the clinical level secondary to the caused protein deficiency, either in function or reduced antigen level in plasma (Koeberl et al, 1990). In general, there is good correlation between the type of mutation (location in the aminoacid position and domain in the protein) and their functional outcome, yielding a predictable clinical severity.…”

“…Different analyses of posttranslational processing and intracellular trafficking revealed that neither mutant was secreted nor accumulated in the intracellular space due to their interaction with chaperones from endoplasmic reticulum (ER) that cause their arrest and lead to their degradation into proteasomes (Enjolras et al, 2004). A related study was carried out for the relevant factor IX mutations identified in Mexican hemophilia B patients that were caused by a recurrent mutagenesis at non-CpG sites (Jaloma-Cruz et al, 2000). They also affected the structurefunction of FIX by changes of a cysteine position in the second epidermal growth factor (EGF2) domain of factor IX gene (C111S and C111Y mutations).…”