Molecular diagnosis of distal renal tubular acidosis in Tunisian patients: proposed algorithm for Northern Africa populations for the ATP6V1B1, ATP6V0A4 and SCL4A1 genes

Background: Primary distal renal tubular acidosis (dRTA) caused by mutations in the genes that codify for the H+ -ATPase pump subunits is a heterogeneous disease with a poor phenotype-genotype correlation. Up to now, large cohorts of dRTA Tunisian patients have not been analyzed, and molecular defects may differ from those described in other ethnicities. We aim to identify molecular defects present in the ATP6V1B1, ATP6V0A4 and SLC4A1 genes in a Tunisian cohort, according to the following algorithm: first, ATP6V1B1 gene analysis in dRTA patients with sensorineural hearing loss (SNHL) or unknown hearing status. Afterwards, ATP6V0A4 gene study in dRTA patients with normal hearing, and in those without any structural mutation in the ATP6V1B1 gene despite presenting SNHL. Finally, analysis of the SLC4A1 gene in those patients with a negative result for the previous studies. Methods: 25 children (19 boys) with dRTA from 20 families of Tunisian origin were studied. DNAs were extracted by the standard phenol/chloroform method. Molecular analysis was performed by PCR amplification and direct sequencing. Results: In the index cases, ATP6V1B1 gene screening resulted in a mutation detection rate of 81.25%, which increased up to 95% after ATP6V0A4 gene analysis. Three ATP6V1B1 mutations were observed: one frameshift mutation (c.1155dupC; p.Ile386fs), in exon 12; a G to C single nucleotide substitution, on the acceptor splicing site (c.175-1G > C; p.?) in intron 2, and one novel missense mutation (c. 1102G > A; p. Glu368Lys), in exon 11. We also report four mutations in the ATP6V0A4 gene: one single nucleotide deletion in exon 13 (c.1221delG; p. Met408Cysfs* 10); the nonsense c.16C > T; p.Arg6*, in exon 3; and the missense changes c.1739 T > C; p.Met580Thr, in exon 17 and c.2035G > T; p.Asp679Tyr, in exon 19. Conclusion: Molecular diagnosis of ATP6V1B1 and ATP6V0A4 genes was performed in a large Tunisian cohort with dRTA. We identified three different ATP6V1B1 and four different ATP6V0A4 mutations in 25 Tunisian children. One of them, c.1102G > A; p.Glu368Lys in the ATP6V1B1 gene, had not previously been described. Among deaf since childhood patients, 75% had the ATP6V1B1 gene c. 1155dupC mutation in homozygosis. Based on the results, we propose a new diagnostic strategy to facilitate the genetic testing in North Africans with dRTA and SNHL.

Una testimonianza silenziosa.Storia della Chiesa cattolica in Tunisia dal Trattato del Bardo alla ‘rivoluzione dei gelsomini’

The work examines the change involving the Church in Tunisia from the period of the Protectorate to the present through the fundamental moments of independence (1956) and the signing of the ‘Modus vivendi’ (1964). In the first structure of the “modern” Church, a fundamental role was played by the complex figure of the French Cardinal Charles-Allemand Lavigerie who, while giving strong impulse to setting up disinterested charitable social initiatives by the congregations (Pères Blancs, Soeurs Blanches and others), also represented the ideal of the ‘evangelizing’ (as well as colonial) Church which, despite its declared will to avoid proselytism, almost inevitably tended to slip into it. During the French Protectorate (1881-1956) the ecclesiastic institution concentrated strongly on itself, with little heed for the sensitivity of its host population, and developed its activities as if it were in a European country. From the social standpoint, the Church was mostly involved in teaching, which followed the French model, and health facilities. In the Church only the Pères Blancs missionaries were sincerely committed to promoting awareness of the local context and dialogue with the Muslims. The Catholic clergy in the country linked its religious activity close to the policy of the Protectorate, in the hope of succeeding in returning to the ancient “greatness of the African Church”, as the Eucharistic Congress in Carthage in 1930 made quite clear. The Congress itself planted the first seed in the twentyfive- year struggle that led the Tunisian population to independence in 1956 and the founding of the Republic in 1957. The conquest of independence and the ‘Modus vivendi’ marked a profound change in the situation and led to an inversion of roles: the Catholic community was given the right to exist only on the condition that it should not interfere in Tunisian society. The political project of Bourguiba, who led the Republic from 1957 to 1987, aimed to create a strongly egalitarian society, with a separation between political and religious powers. In particular, in referring to the Church, he appeared as a secularist with no hostility towards the Catholics who were, however, considered as “cooperators”, welcome so long as they were willing to place their skills at the service of the construction of the state. So, in the catholic Community was a tension between the will of being on the side of the country and that of conserving a certain distance from it and not being an integral part of it. In this process of reflection, the role of the Second Vatican Council was fundamental: it spread the idea of a Church open to the world and the other religions, in particular to Islam: the teaching of the Council led the congregations present in the country to accept the new condition. This new Church that emerged from the Council saw some important events in the process of “living together”, of “cultural mixing” and the search for a common ground between different realities. The almost contemporary arrival of Arab bishops raised awareness among the Tunisians of the existence of Christian Arabs and, at the same time, the Catholic community began considering their faith in a different way. In the last twenty years the situation has continued to change. Side by side with the priests present for decades or even those born there, some new congregations have begun to operate, albeit in small numbers: they have certainly revitalized the community of the faithful, but they sometimes appear more devoted to service “within” the Church, than to services for the population, and are thus characterized by exterior manifestations of their religion. This sort of presence has made it possible for Bourguiba's successor, Ben Ali (president from 1987 to 2011), to practice forms of tolerance even more clearly, but always limited to formal relations; the Tunisians are still far from having a real understanding of the Catholic reality, with certain exceptions connected to relations on a personal and not structured plane, as was the case in the previous period. The arrival of a good number of young people from sub-Saharan Africa, most of all students, belonging to the JCAT, and personnel of the BAD has “Africanized” the Church in Tunisia and has brought about an increase in Christians' exterior manifestations; but this is a visibility that is not blatant but discreet, with the implicit risk of the Church continuing to be perceived as a sort of exterior body, alien to the country; nor can we say, lacking proper documentation, how it will be possible to build a bridge between different cultures through the “accompaniment” of Christian wives of Tunisians. Today, the Church is living in a country that has less and less need of it; its presence, in the schools and in health facilities, is extremely reduced. And also in other sectors of social commitment, such as care for the disabled, the number of clergymen involved is quite small. The ‘revolution’ in 2011 and the later developments up to the present have brought about another socio-political change, characterized by a climate of greater freedom, but with as yet undefinable contours. This change in the political climate will inevitable have consequences in Tunisia’s approach to religious and cultural minorities, but it is far too soon to discuss this on the historical and scientific planes.

Búsqueda de selección en el polimorfismo 677C>T (c.665C>T) del gen de la metilentetrahidrofolato reductasa (MTHFR) en una población Colombiana

Se realizó un estudio genético – poblacional en dos grupos etarios de población colombiana con la finalidad de evaluar las diferencias genéticas relacionadas con el polimorfismo MTHFR 677CT en busca de eventos genéticos que soporten la persistencia de este polimorfismo en la especie humana debido que este ha sido asociado con múltiples enfermedades. De esta manera se genotipificaron los individuos, se analizaron los genotipos, frecuencias alélicas y se realizaron diferentes pruebas genéticas-poblacionales. Contrario a lo observado en poblaciones Colombianas revisadas se identificó la ausencia del Equilibrio Hardy-Weinberg en el grupo de los niños y estructuras poblacionales entre los adultos lo que sugiere diferentes historias demográficas y culturales entre estos dos grupos poblacionales al tiempo, lo que soporta la hipótesis de un evento de selección sobre el polimorfismo en nuestra población. De igual manera nuestros datos fueron analizados junto con estudios previos a nivel nacional y mundial lo cual sustenta que el posible evento selectivo es debido a que el aporte de ácido fólico se ha incrementado durante las últimas dos décadas como consecuencia de las campañas de fortificación de las harinas y suplementación a las embarazadas con ácido fólico, por lo tanto aquí se propone un modelo de selección que se ajusta a los datos encontrados en este trabajo se establece una relación entre los patrones nutricionales de la especie humana a través de la historia que explica las diferencias en frecuencias de este polimorfismo a nivel espacial y temporal.  

Búsqueda de mutaciones en el gen foxo4 en pacientes con falla ovárica prematura no-sindrómica

FOXO4 constitutes a coherent candidate gene associated with premature ovarian failure (POF) pathogenesis. This study sequenced the coding and exon-flanking regions of this gene in a panel of 116 POF patients and 143 controls of Tunisian origin. In both groups, the IVS2 + 41T > G sequence variant was identified. It is concluded that coding mutations of FOXO4 should not be a common cause of the disease in women from the Tunisian population. However, this study cannot exclude that FOXO4 dysfunctions, originated from open reading frame or promoter sequence variations, might be associated with the pathogenesis of the disease in other ethnical groups.

Allozyme and mtDNA variation of white seabream Diplodus sargus populations in a transition area between western and eastern Mediterranean basins (Siculo-Tunisian Strait)

To investigate the possible influence of the Siculo-Tunisian Strait on the genetic structure of white seabream Diplodus sargus, 13 polymorphic allozyme loci and a fragment of the cytochrome b mitochondrial DNA were analysed. Allozyme data indicated a moderate but significant differentiation between some north-eastern (Bizerta, Ghar El Melh Lagoon and Mahdia) and southern (Gabes Gulf and El Biban Lagoon) samples. This heterogeneity was also highlighted after removing PGM* and PGI-1* loci which may be under selection. These results can be explained by the chaotic genetic patchiness hypothesis. In contrast, the mtDNA data indicated genetic homogeneity among localities showing the absence of structure in white seabream populations across the Siculo-Tunisian Strait. Historical demography of this species suggests that it has undergone a recent population expansion as a consequence of a bottleneck event during the Pleistocene glaciations.

Reducing the global burden of depression : population level analysis of intervention cost-effectiveness in 14 world regions

International evidence on the cost and effects of interventions for reducing the global burden of depression remain scarce. Aims: To estimate the population-level cost-effectiveness of evidence-based depression interventions and their contribution towards reducing current burden. Method: Primary-care-based depression interventions were modelled at the level of whole populations in 14 epidemiological subregions of the world. Total population-level costs (in international dollars or I$) and effectiveness (disability adjusted life years (DALYs) averted) were combined to form average and incremental cost-effectiveness ratios. Results: Evaluated interventions have the potential to reduce the current burden of depression by 10–30%. Pharmacotherapy with older antidepressant drugs, with or without proactive collaborative care, are currently more cost-effective strategies than those using newer antidepressants, particularly in lower-income subregions. Conclusions: Even in resource-poor regions, each DALYaverted by efficient depression treatments in primary care costs less than 1 year of average per capita income, making such interventions a cost-effective use of health resources. However, current levels of burden can only be reduced significantlyif there is a substantialincrease substantial increase intreatment coverage.