Main objectives:
Usher syndrome is the most common autosomal recessive disorder that associates hearing loss and retinitis pigmentosa. It is clinically and genetically heterogeneous and three phenotypic groups are distinguished based on the severity and progression of hearing loss and the presence or absence of vestibular impairment. Nine genes are known to be involved in the three clinical subtypes of the disease, five in Usher type I, the most severe form, three in Usher type II, the most common form, and one in Usher type III. The knowledge of the molecular causes of this disease is the first step to improve our understanding of the physiopathology. This will become crucial if gene-specific therapy becomes available in the future.
Most of the identified mutations are private or appear at a low frequency. Our aim is to characterise them, and offer to the scientific community a significant number of newly classified variants. These data are useful to genetic counselling, molecular diagnosis and fundamental research. We receive patient samples from all other France, and also from Italy, Portugal, Austria. We have developed an original approach that allows the identification of mutations in 90 and 70 % of Usher patients type I and II, respectively. This approach includes indirect studies prior mutation analysis to identify candidate gene(s). When the indirect analyses are not informative, the most mutated exons of each gene are screened by direct sequencing, allowing, in most cases, at least the identification of the responsible gene. When available, the family is also studied, in order to establish the allelic repartition of the mutations.
Variants can be assessed using different techniques:
-position in cis or in trans of the different alterations
-epidemiologic studies
-in silico prediction, using different tools such as:
• assessment of the importance of the wild-type residue based on a) alignments of orthologs and alignments of common structural domains in different proteins, and b) 3D modeling
• assessment of the potential destabilising effect of the mutant residue based on a) physicochemical properties, b) secondary structure predictions and c) 3D modeling
These data are then added in UMD databases. These are LSDBs, developed and maintained in our lab, and recognized by several organisms (HUGO, HGVS) as a reference tool. The main genes involved in Usher syndrome have their dedicated database. These databases are available to the scientific community (http://194.167.35.168/usher.html) and are regularly updated. »