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A STUDY OF THE MITOCHONDRIAL MUTATION A1555G

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Mahmoud Fassad

on 7 April 2015

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Transcript of A STUDY OF THE MITOCHONDRIAL MUTATION A1555G

To search for the A1555G mutation among patients with non-syndromic SNHL, which will allow accurate diagnosis and better GC since the maternal relatives of patients with the mutation will be at risk for aminoglycoside induced deafness.



Methods
Subjects
PCR-RFLP
Confirmation
The positive results of PCR-RFLP were confirmed by direct sequencing.
A study of the mitochondrial mutation A1555G among patients with non-syndromic sensorineural hearing loss

By: Mahmoud Raafat Fassad
بساا
لألألألأ
لأGENETIC COUNSELING
In Egypt, it is estimated that for every 100,000 children (under 14 years old), there are more than 800 with hearing. impairment
Background
It is important to note that the presence of an environmental cause does not necessarily exclude the existence of an underlying genetic predisposition. The genetic analysis of patients with hearing loss due to environmental causes commonly identifies pathogenic mutations.
Etiology of Deafness
Various mutations in mtDNA, causing both syndromic and non-syndromic hearing loss, have been identified .
Mutations are often homoplasmic or at high levels of heteroplasmy
Genetics of HL
Mitochondrial HL
Mitochondrial haplotypes
It was first discovered in a large Arab-Israeli family. Subsequently, it was found in various ethnic groups from Europe, Asia and Africa, with a variable prevalence .
A1555G mtDNA mutation
Hearing loss
The A1555G mutation produces a variable clinical phenotype ranging from severe congenital deafness to completely normal hearing.

A1555G
It is known that nucleotide 1555 is important for the action of aminoglycosides:
Aminoglycosides ototoxicity
The presence of A1555G makes the 2ry structure of RNA resemble more closely the corresponding region of E. coli 16S rRNA and consequently leads to defects in mitochondrial translation.
The new nucleotide pair in the 12S rRNA is also expected to create a binding site for aminoglycosides, which facilitates the interaction with these drugs.

Thus, exposure to aminoglycosides causes hearing loss in individuals carrying A1555G mutation.
Aim of the Work

97 patients from seventy six families with bilateral non-syndromic sensorineural hearing loss.
The region of 12S rRNA gene that encloses the A1555G mutation was amplified.
Presence of G at the position 1555 creates a restriction site HaeIII(GGCC/CCGG). Thus, the PCR product was digested by restriction endonuclease enzyme HaeIII.
The PCR product contains another HaeIII site, which serves as a control of the enzyme digestion.

Interpretation of molecular results
Biological data
Results
Biological Data
The genetic nature of hearing loss
Expected risk of recurrence
Possible preventive measures
The available interventions
The importance of follow up
Biological Data
Clinical data
Clinical Data
Audiological Characteristics
Molecular results
Molecular results
Sequencing
To estimate the local population prevalence of A1555G mutation among a sample of the Egyptian population.
Conclusions
The mitochondrial A1555G mutation is not prevalent among the Egyptian patients with SNHL.



The A1555G mutation has been detected in only one of the studied patients (1.3%) and in none of the 300 controls, indicating that it might be rather uncommon among Egyptians.
Even in absence of exposure to aminoglycosides, the mitochondrial A1555G mutation is one of the potential causes of non-syndromic sensorineural hearing loss in the Egyptian population.

The PCR/RFLP molecular techniques, with the protocol used in the study, are easy, reliable, cheap and simple methods for tracking the A1555G mutation, helping the molecular investigation of the hearing loss
Recommendations
The A1555G mtDNA mutation should be a part of any genetic screening of hearing loss in cases where a maternal mode of transmission is apparent, followed by genetic counseling of affected patients and their families to prevent aminoglycoside induced hearing impairment of maternal relatives.

Larger sample size (with special emphasis on postlingual hearing loss) is needed for more reproducible results and a better estimation of the prevalence of the A1555G mtDNA mutation in both patients with hearing loss and normal Egyptian population.

It is important to initiate researches to study the mechanism underlying hearing loss in patients carrying A1555G mutation with exposure to aminoglycoside antibiotics and to identify modifying factors of its phenotypic manifestations.

Generalized public health education is recommended to explain to the public and health professionals the benefits of genetic services for children with hearing loss and their families
Discussion
Hearing loss is the most common form of neurosensory impairment in human
In 2012, WHO stated that 360 million persons in the world have disabling hearing loss (5.3% of the world’s population).
Deafness is a clinically and genetically heterogeneous disorder with various genetic and environmental causes.
Although the majority of hereditary hearing loss is due to nuclear gene mutations, it has become clear the significant contribution of mitochondrial genes.
Hearing loss can also be the sole symptom of mitochondrial disease.
Deafness associated mtDNA mutations usually occurs in the genes encoding components of the protein-synthesizing apparatus: rRNAs and tRNAs.
Phenotypic expression of these mtDNA mutations requires the contribution of other factors such as:
Nuclear modifier genes
Environmental factors
The first mitochondrial mutation shown to cause non-syndromic hearing loss in humans was the A1555G mutation in the small ribosomal RNA gene (12S rRNA).
Mutation A1555G resides in a highly conserved region and a functionally well-characterized domain, which is an essential part of the decoding site of the small ribosomal subunit.
Cases
Control
300 individuals with normal hearing
Genetic counseling
Molecular genetic testing (PCR-RFLP & Sequencing)
Assessment of peripheral hearing sensitivity
Clinical genetic evaluation
Pedigree construction
Detailed history taking including the medical, genetic and family history
Full transcript