Otosclerosis is a common disorder of the otic capsule resulting in hearing impairment in 0.3-0.4% of the Caucasian population. The aetiology of the disease remains unclear. In most cases, otosclerosis can be considered as a complex disease. In some cases, the disease is inherited as an autosomal dominant trait, sometimes with reduced penetrance. To date, seven autosomal dominant loci have been reported, but none of the disease-causing genes has been identified. In this study, we present the results of a genome-wide linkage analysis in a large Tunisian family segregating autosomal dominant otosclerosis. Linkage analysis localised the responsible gene to chromosome 9p13.1-9q21.11 with a maximal LOD score of 4.13, and this locus was named OTSC8. Using newly generated short tandem repeat polymorphism markers, we mapped this new otosclerosis locus to a 34.16 Mb interval between the markers D9S970 and D9S1799. This region comprises the pericentromeric region on both arms of chromosome 9, a highly complex region containing many duplicated sequences.

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Otosclerosis is caused by an abnormal bone homeostasis of the otic capsule resulting in a conductive hearing loss when the free motion of the stapes is compromised. An additional sensorineural hearing loss arises in some patients, most likely due to otosclerotic foci that invade the cochlear endosteum. Otosclerosis is a very common hearing impairment among Caucasians with a prevalence of about 0.3-0.4% among white adults. In the majority of cases, otosclerosis can be considered as a complex disease, caused by both genetic as environmental factors, but autosomal dominant forms of otosclerosis exist. However, families large enough for genetic analysis are very rare and often show reduced penetrance. To date five loci have been reported, but none of the genes have been cloned yet. In this study, we analyzed two new autosomal dominant otosclerosis families from Tunisia, and genotyped them with microsatellite markers for the known loci, the collagen genes COL1A1 and COL1A2, and NOG gene. In the family LK, linkage to all known loci was excluded. However, the family LS shows suggestive linkage to the OTSC3 region on chromosome 6p21.3-p22.3. This result points out that, besides the five reported loci, there must be at least one additional locus for autosomal dominant otosclerosis.

In conclusion, the data suggest that a variation in class I HLA antigens could be a genetic factor involved in susceptibility to otosclerosis in the Tunisian population.

Background Dipeptidyl peptidase III (DPPIII) member of M49 peptidase family is a zinc-dependent metallopeptidase that cleaves dipeptides sequentially from the N-terminus of its substrates. In Leishmania, DPPIII, was reported with other peptidases to play a significant role in parasites’ growth and survival. In a previous study, we used a coding sequence annotated as DPPIII to develop and evaluate a PCR assay that is specific to dermotropic Old World (OW) Leishmania species. Thus, our objective was to further assess use of this gene for Leishmania species identification and for phylogeny, and thus for diagnostic and molecular epidemiology studies of Old World Leishmania species. Methodology Orthologous DDPIII genes were searched in all Leishmania genomes and aligned to design PCR primers and identify relevant restriction enzymes. A PCR assays was developed and seventy-two Leishmania fragment sequences were analyzed using MEGA X genetics software to infer evolution and phylogenetic relationships of studied species and strains. A PCR-RFLP scheme was also designed and tested on 58 OW Leishmania strains belonging to 8 Leishmania species and evaluated on 75 human clinical skin samples. Findings Sequence analysis showed 478 variable sites (302 being parsimony informative). Test of natural selection (dN-dS) (-0.164, SE = 0.013) inferred a negative selection, characteristic of essential genes, corroborating the DPPIII importance for parasite survival. Inter- and intra-specific genetic diversity was used to develop universal amplification of a 662bp fragment. Sequence analyses and phylogenies confirmed occurrence of 6 clusters congruent to L. major, L. tropica, L. aethiopica, L. arabica, L. turanica, L. tarentolae species, and one to the L. infantum and L. donovani species complex. A PCR-RFLP algorithm for Leishmania species identification was designed using double digestions with HaeIII and KpnI and with SacI and PvuII endonucleases. Overall, this PCR-RFLP yielded distinct profiles for each of the species L. major, L. tropica, L. aethiopica, L. arabica and L. turanica and the L. (Sauroleishmania) L. tarentolae. The species L. donovani, and L. infantum shared the same profile except for strains of Indian origin. When tested on clinical samples, the DPPIII PCR showed sensitivities of 82.22% when compared to direct examination and was able to identify 84.78% of the positive samples. Conclusion The study demonstrates that DPPIII gene is suitable to detect and identify Leishmania species and to complement other molecular methods for leishmaniases diagnosis and epidemiology. Thus, it can contribute to evidence-based disease control and surveillance.