Dr Paolo Gasparini, a medical geneticist and Head of Medical Genetics Department, University of Trieste, Italy, working with a group of Italian researchers, all of whom have long standing experience on the genetics of hearing loss, recently made headway in genetics research thanks to QNRF funding.
In collaboration with a team of investigators from Hamad Medical Center, Qatar (HMC), the research team identified the mutated gene associated with hearing loss. They also found mutations of that gene and of other genes, all related to characters and disorders typical of the Qatari population. The development has significant relevance not only for patients in Qatar, but also for patients worldwide because this gene has never before been associated with the disease.
The work has been carried out as a collaborative project between Dr Gasparini and colleagues from HMC, namely Dr. Ramin Badii and Dr. Moza Al-Kowari from the Molecular Genetics Lab and Dr. Khalid Abdul Hadi, Head of the Ear, Nose and Throat (ENT) Department.
Hereditary hearing loss (HHL) is a disease particularly prevalent in Qatar due to the high level of consanguinity in the population and a common disorder accounting for at least 60% of pre-lingual deafness [in children].
The Qatari population structure reveals three clear clusters of genotypes consistent with Arabian origin, an eastern or Persian origin, and individuals with African admixture (Hunter-Zinck et al, 2010). The extent of linkage disequilibrium (LD) was found to be greater than that of African populations, and large regions of homozygosity in some individuals reflect substantial consanguinity. These molecular findings further confirm previous epidemiological studies showing that in the Qatari population there is a rate of consanguinity in the present generation of 51% – for comparison purposes, that is greater than Oman but lower than Saudi Arabia. First cousins and double first cousins consanguineous marriages are very common in Qatar, with the current generation of consanguineous parents showing a higher risk for most diseases including cancer, mental disorders, heart diseases, gastro-intestinal disorders, hypertension, diabetes mellitus, and NSHHL. Regarding HHL, a 5.2% (compared to the global norm) prevalence of hearing loss was reported with parental consanguinity more common among affected individuals as compared with unaffected individuals (60.5% versus 25.3%) (Bener et al, 2005).
Data were collected from 126 Qatari patients (58 males and 68 females) belonging to inbred families, showing an autosomal recessive pattern of inheritance (96%). Fifty-three patients were less than 10 years old, 55 in the age range of 10 to 20 years, while 18 were aged between 20 and 30 years. All subjects had moderate to severe sensorineural hearing loss and were screened for GJB2 mutations, GJB6 deletion, and for A1555G mitochondrial mutation.
After a molecular screening of the most common genes demonstrating their low impact in Qatari patients, the team developed a combined strategy using both genetic linkage study and exome sequencing to identify new genes. It was then that the advance was made. A new gene causing hearing loss, named BDP1 was identified in patients from a consanguineous family of second degree, showing bilateral, postlingual and sensorineural moderate to severe hearing impairment. The mutation disrupts the termination codon of the transcript resulting in an elongation of 11 residues of the BDP1 protein. Immunohistochemistry studies carried out in the inner ear of a mouse showed BDP1 expression within inner ear cells. “This is very exciting as the identification of the BDP1 gene increases our knowledge on the molecular bases of HHL, opening new perspectives for the diagnosis and treatment of this disease in the Qatari population” said Dr Gasparini. “At first I thought I would have only the one common gene, but this is not the case – there are many and this demonstrates that such diversification reduces the risk associated with consanguinity” he added.
“Being recessive, the disease starts at birth”, Dr Gasparini said, “but inheritance of the gene is not gender related. Currently, there is no indication of other problems and, although vertigo is a compounding factor the vast majority does not show any vestibular signs.”
The work has now been published in one of the largest scientific journals, PLOS One, and can be accessed by clicking here.
The work has been funded by QNRF grant NPRP 08-084-3-032
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