A South African family with the mitochondrial A1555G mutation on haplogroup L0d

The most common mutation associated with aminoglycoside-induced deafness is A1555G and it has been found in diverse populations worldwide. In the present study we investigated a large South African family known to harbour A1555G. A total of 97 family members were genotyped using the SNaPshot technique and 76 were found to be A1555G-positive (on haplogroup L0d) and are therefore at risk of developing irreversible hearing loss. The method worked equally well on both blood (from adults) and buccal swabs (from children). Variants in the tRNA^Ser(UCN), A10S in TRMU and 35delG in GJB2 genes were shown not to act as genetic modifiers in this family. It is important to identify mutation-positive individuals and inform them of their increased risk of developing aminoglycoside-induced deafness especially in a setting like South Africa where these drugs are still commonly used because of their efficacy and cost-effectiveness as a treatment for resistant forms of tuberculosis.     

Mutation analysis of mitochondrial 12S rRNA gene in Polish patients with non-syndromic and aminoglycoside-induced hearing loss

Mutations in mitochondrial DNA have been reported as associated with non-syndromic and aminoglycoside-induced hearing loss. In the present study, we have performed mutational screening of entire 12S rRNA gene in 250 unrelated patients with non-syndromic and aminoglycoside-induced hearing loss. Twenty-one different homoplasmic sequence variants were identified, including eight common polymorphisms, one deafness-associated mutation m.1555 A>G and three putatively pathogenic variants: m.669 T>C, m.827 A>G, m.961 delT+C(n)ins. The incidence of m.1555 A>G was estimated for 3.6% (9/250); however, where aminoglycoside exposure was taken as a risk factor, the frequency was 5.5% (7/128). Substitution m.669 T>C was identified only in patients with hearing impairment and episode of aminoglycoside exposure, which may suggest that such additional risk factors must appear to induce clinical phenotype. Moreover, two 12S rRNA sequence variants: m.988 G>A and m.1453 A>G, localized at conserved sites and affected RNA secondary structure, may be new candidates for non-syndromic and aminoglycoside-induced hearing loss associated mutations.     

Study of modifiers factors associated to mitochondrial mutations in individuals with hearing impairment

Hearing impairment is the most prevalent sensorial deficit in the general population. Congenital deafness occurs in about 1 in 1000 live births, of which approximately 50% has hereditary cause in development countries. Non-syndromic deafness can be caused by mutations in both nuclear and mitochondrial genes. Mutations in mtDNA have been associated with aminoglycoside-induced and non-syndromic deafness in many families worldwide. However, the nuclear background influences the phenotypic expression of these pathogenic mutations. Indeed, it has been proposed that nuclear modifier genes modulate the phenotypic manifestation of the mitochondrial A1555G mutation in the MTRNR1 gene. The both putative nuclear modifiers genes TRMU and MTO1 encoding a highly conserved mitochondrial related to tRNA modification. It has been hypothesizes that human TRMU and also MTO1 nuclear genes may modulate the phenotypic manifestation of deafness-associated mitochondrial mutations. The aim of this work was to elucidate the contribution of mitochondrial mutations, nuclear modifier genes mutations and aminoglycoside exposure in the deafness phenotype. Our findings suggest that the genetic background of individuals may play an important role in the pathogenesis of deafness-associated with mitochondrial mutation and aminoglycoside-induced.     

Investigation of the A1555G mutation in mitochondrial DNA (MT-RNR1) in groups of Brazilian individuals with nonsyndromic deafness and normal-hearing

BACKGROUND:

Mutations of mitochondrial DNA were described into two genes: The mitochondrially encoded 12S RNA (MT-RNR1) and the mitochondrially encoded tRNA serine^ucn (MT-TS1). The A1555G mutation in MT-RNR1 gene is a frequent cause of deafness in different countries.

AIM:

The aim of this work was to investigate the frequency of the A1555G mutation in the MT-RNR1 gene in the mitochondrial DNA in Brazilians individuals with nonsyndromic deafness, and listeners.

MATERIALS AND METHODS:

DNA samples were submitted to polymerase chain reaction and to posterior digestion with the Hae III enzyme.

RESULTS:

Seventy eight (78) DNA samples of deaf individuals were analyzed; 75 showed normality in the region investigated, two samples (2.5%) showed the T1291C substitution, which is not related to the cause of deafness, and one sample (1.3%) showed the A1555G mutation. Among the 70 non-impaired individuals no A1555G mutation or T1291C substitution was found.

CONCLUSION:

We can affirm that A1555G mutation is not prevalent, or it must be very rare in normal-hearing subjects in the State of Paraná, the south region of Brazil. The A1555G mutation frequency (1.3%) found in individual with nonsyndromic deafness is similar to those found in other populations, with nonsyndromic deafness. Consequently, it should be examined in deafness diagnosis. The investigation of the A1555G mutation can contribute towards the determination of the nonsyndromic deafness etiology, hence, contributing to the correct genetic counseling process.     

Mutational analysis of the mitochondrial 12S rRNA and tRNASer(UCN) genes in Tunisian patients with nonsyndromic hearing loss

We explored the mitochondrial 12S rRNA and the tRNASer(UCN) genes in 100 Tunisian families affected with NSHL and in 100 control individuals. We identified the mitochondrial A1555G mutation in one out of these 100 families and not in the 100 control individuals. Members of this family harbouring the A1555G mutation showed phenotypic heterogeneity which could be explained by an eventual nuclear-mitochondrial interaction. So, we have screened three nuclear genes: GJB2, GJB3, and GJB6 but we have not found correlation between the phenotypic heterogeneity and variants detected in these genes. We explored also the entire mitochondrial 12S rRNA and the tRNASer(UCN) genes. We detected five novel polymorphisms: T742C, T794A, A813G, C868T, and C954T, and 12 known polymorphisms in the mitochondrial 12S rRNA gene. None of the 100 families or the 100 controls were found to carry mutations in the tRNASer(UCN) gene. We report here the first mutational screening of the mitochondrial 12S rRNA and the tRNASer(UCN) genes in the Tunisian population which describes the second family harbouring the A1555G mutation in Africa and reveals novel polymorphisms in the mitochondrial 12S rRNA gene.     

Mutational analysis of the mitochondrial tRNALeu(UUR) gene in Tunisian patients with mitochondrial diseases

The mitochondrial tRNA(Leu(UUR)) gene (MTTL) is a hot spot for pathogenic mutations that are associated with mitochondrial diseases with various clinical features. Among these mutations, the A3243G mutation was associated with various types of mitochondrial multisystem disorders, such as MIDD, MELAS, MERRF, PEO, hypertrophic cardiomyopathy, and a subtype of Leigh syndrome. We screened 128 Tunisian patients for the A3243G mutation in the mitochondrial tRNA(Leu(UUR)) gene. This screening was carried out using PCR-RFLP with the restriction endonuclease ApaI. None of the 128 patients or the 100 controls tested were found to carry the mitochondrial A3243G mutation in the tRNA(Leu(UUR)) gene in homoplasmic or heteroplasmic form. After direct sequencing of the entire mitochondrial tRNA(Leu(UUR)) gene and a part of the mitochondrial NADH dehydrogenase 1, we found neither mutations nor polymorphisms in the MTTL1 gene in the tested patients and controls, and we confirmed the absence of the A3243G mutation in this gene. We also found a T3396C transition in the ND1 gene in one family with NSHL which was absent in the other patients and in 100 controls. Neither polymorphisms nor other mutations were found in the mitochondrial tRNA(Leu(UUR)) gene in the tested patients.     

In vivo effects of chronic contamination with depleted uranium on vitamin D3 metabolism in rat

The extensive use of depleted uranium (DU) in today's society results in the increase of the number of human population exposed to this radionuclide. The aim of this work was to investigate in vivo the effects of a chronic exposure to DU on vitamin D₃ metabolism, a hormone essential in mineral and bone homeostasis. The experiments were carried out in rats after a chronic contamination for 9 months by DU through drinking water at 40 mg/L (1 mg/rat/day). This dose corresponds to the double of highest concentration found naturally in Finland. In DU-exposed rats, the active vitamin D (1,25(OH)₂D₃) plasma level was significantly decreased. In kidney, a decreased gene expression was observed for cyp24a1, as well as for vdr and rxrα, the principal regulators of CYP24A1. Similarly, mRNA levels of vitamin D target genes ecac1, cabp-d28k and ncx-1, involved in renal calcium transport were decreased in kidney. In the brain lower levels of messengers were observed for cyp27a1 as well as for lxrβ, involved in its regulation. In conclusion, this study showed for the first time that DU affects both the vitamin D active form (1,25(OH)₂D₃) level and the vitamin D receptor expression, and consequently could modulate the expression of cyp24a1 and vitamin D target genes involved in calcium homeostasis.     

Mutational spectrum of Xeroderma pigmentosum group A in Egyptian patients

Xeroderma pigmentosum (XP) is a rare autosomal recessive hereditary disease characterized by hyperphotosensitivity, DNA repair defects and a predisposition to skin cancers. The most frequently occurring type worldwide is the XP group A (XPA). There is a close relationship between the clinical features that ranged from severe to mild form and the mutational site in XPA gene. The aim of this study is to carry out the mutational analysis in Egyptian patients with XP-A. This study was carried out on four unrelated Egyptian XP-A families. Clinical features were examined and direct sequencing of the coding region of XPA gene was performed in patients and their parents. Direct sequencing of the whole coding region of the XPA gene revealed the identification of two homozygous nonsense mutations: (c.553C>T; p.(Gln185*)) and (c.331G>T; p.(Glu111*)), which create premature, stop codon and a homodeletion (c.374delC: p.Thr125Ilefs*15) that leads to frameshift and premature translation termination. We report the identification of one novel XPA gene mutation and two known mutations in four unrelated Egyptian families with Xermoderma pigmentosum. All explored patients presented severe neurological abnormalities and have mutations located in the DNA binding domain. This report gives insight on the mutation spectrum of XP-A in Egypt. This would provide a valuable tool for early diagnosis of this severe disease.