Factor VIII haplotypes frequencies in Tunisian hemophiliacs A

<p>Abstract</p> <p>Background</p> <p>The development of inhibitors against factor 8 (F8) is the most serious complication of replacement therapy with F8 in children with severe hemophilia. It was suggested that mismatched F8 replacement therapy may be a risk factor for the development of anti-factor F8 alloantibodies. Recently four single nucleotide polymorphisms (SNPs) encoding six distinct haplotypes, designated H1 through H6, were studied in different populations. Two SNPs are components of the A2 and C2 immunodominant-inhibitor epitopes.</p> <p>The aim of this study is to determine the different types of haplotypes in relation with inhibitors developments and their frequencies in our Tunisian hemophiliac population.</p> <p>Materials and methods</p> <p>95/116 Tunisian patients with hemophilia A undergoing treatment at Hemophilia Treatment Center, Aziza Othmana hospital, participate in this study. Among them only six patients develop inhibitors. The four SNPs were amplified and sequenced.</p> <p>Results and Discussion</p> <p>In a total of 77 patients, we identified the H1, H2, H3 and the infrequent H5 haplotypes. The H1 and H2 haplotypes, which have the same amino acid sequence in the recombinant F8 molecules used clinically, are the most represented with the frequency of 0.763 and 0.157 respectively. This distribution is almost similar to that of Caucasians in which the frequencies are respectively 0.926 and 0.074, whereas it is 0.354 and 0.374 among Subsaharians. Four patients with inhibitors studied here have the H1 haplotype. For one patient who has a large deletion including the exon 10 we can't identify his haplotype. Theses frequencies may explain partially the low level of inhibitors in our patients.</p

Increased <i>CPA6 </i>promoter methylation in focal epilepsy and in febrile seizures

Focal epilepsy (FE) is one of the most common forms of adult epilepsy and is usually regarded as a multifactorial disorder. Febrile seizures (FS) often appear during childhood in a subtype of FE patients, i.e. with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS). FS are the most common human convulsive event associated with fever. Genetic evidences for FS have suggested a complex mode of inheritance. Until now, to investigate genes at the genomic level, linkage analysis of familial forms and association studies have been performed, but nothing conclusive has been clearly related to FE and FS. As complex disorders, environmental factors might play a crucial role through epigenetic modification of key candidate genes such as CPA6, which encodes Carboxypeptidase A6, an extracellular protein. Therefore, we assessed DNA methylation in promoter of CPA6. In 186 FE patients and 92 FS patients compared to 93 healthy controls and 42 treated controls with antiepileptic drugs (AEDs), we found significant higher levels of methylation for epileptic patients. Methylation status were 3.4% (±3.2%) for FE cases and 4.3% (±3.5%) for FS cases, whereas healthy individuals and treated controls with AEDs showed a level of 0.8% (±2.9%) and 1.5% (±3.9%), respectively (p≤0.001 for all comparisons). These results let growing evidence for DNA methylation involvment in FE and FS

A new locus on chromosome 22q13.31 linked to recessive genetic epilepsy with febrile seizures plus (GEFS+) in a Tunisian consanguineous family

BACKGROUND: Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with extremely variable expressivity. The aim of our study was to identify the responsible locus for GEFS+ syndrome in a consanguineous Tunisian family showing three affected members, by carrying out a genome-wide single nucleotide polymorphisms (SNPs) genotyping followed by a whole-exome sequencing. We hypothesized an autosomal recessive (AR) mode of inheritance. RESULTS: Parametric linkage analysis and haplotype reconstruction identified a new unique identical by descent (IBD) interval of 527 kb, flanking by two microsatellite markers, 18GTchr22 and 15ACchr22b, on human chromosome 22q13.31 with a maximum multipoint LOD score of 2.51. Our analysis was refined by the use of a set of microsatellite markers. We showed that one of them was homozygous for the same allele in all affected individuals and heterozygous in healthy members of this family. This microsatellite marker, we called 17ACchr22, is located in an intronic region of TBC1D22A gene, which encodes a GTPase activator activity. Whole-exome sequencing did not reveal any mutation on chromosome 22q13.31 at the genome wide level. CONCLUSIONS: Our findings suggest that TBC1D22A is a new locus for GEFS+