Clinical and Genetic Heterogeneity of Inherited Autosomal Recessive Susceptibility to Disseminated<i>Mycobacterium bovis</i>Bacille Calmette‐Guérin Infection

Elloumi-Zghal, Houda; Barbouche, Mohamed Ridha; Chemli, J.; Béjaoui, Mohamed; Harbi, A.; Snoussi, N.; Abdelhak, Sonia; Dellagi, Koussay

doi:10.1086/340510

Cited by 80 publications

(75 citation statements)

References 26 publications

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“…The present study demonstrates that, in spite of the high rate of endogamous marriages in Tunisia, there was a genetic and a mutational heterogeneity affecting the Tunisian MGA1 patients, confirming previous data on several Mendelian diseases affecting the Tunisian population (Elloumi-Zghal et al 2002;Bouchlaka et al 2003, Charfeddine et al 2003). The characterization of new genes and new mutations responsible for MGA1 will, in the future, yield new biological insights and a better comprehension of all the steps involved in the transport of Vit B12 and also facilitate a more exact diagnosis of new suspected cases at an earlier stage of the disease, which is important for the appropriate treatment.…”

Section: Discussionsupporting

confidence: 91%

Genetic heterogeneity of megaloblastic anaemia type 1 in Tunisian patients

Bouchlaka

Maktouf

Mahjoub³

et al. 2007

J Hum Genet

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Megaloblastic anaemia 1 (MGA1) is a rare autosomal recessive condition characterized by selective intestinal vitamin B12 malabsorption and proteinuria. More than 200 MGA1 patients have been identified worldwide, but the disease is relatively prevalent in Finland, Norway and several Eastern Mediterranean regions. MGA1 is genetically heterogeneous and can be caused by mutations in either the cubilin (CUBN) or the amnionless (AMN) gene. In the present study we investigated the molecular defect underlying MGA1 in nine Tunisian patients belonging to six unrelated consanguineous families. Haplotype and linkage analyses, using microsatellite markers surrounding both CUBN and AMN genes, indicated that four out of the six families were likely to be linked to the CUBN gene. Patients from these families were screened for the Finnish, Mediterranean and Arabian mutations already published. None of the screened mutations could be detected in our population. One family showed a linkage to AMN gene. Direct screening of the AMN gene allowed the identification of the c.208-2A>G mutation, previously described in a Jewish Israeli patient of Tunisian origin and in Turkish patients. This suggests that the c.208-2A>G mutation may derive from a single Mediterranean founder ancestor. For the last family, haplotype analysis excluded both CUBN and AMN genes, suggesting the existence of a third locus that may cause MGA1.

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Section: Discussionsupporting

confidence: 91%

Genetic heterogeneity of megaloblastic anaemia type 1 in Tunisian patients

Bouchlaka

Maktouf

Mahjoub³

et al. 2007

J Hum Genet

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“…These findings further delineate the genetic heterogeneity of rare autosomal recessive diseases in Tunisia, as reported previously for different conditions. [22][23][24][25][26] Compared with the other two genes known to cause achromatopsia CNGA3 and CNGB3, GNAT2 is only a minor achromatopsia locus, which account for 2% of the cases. 7 As this is the largest sibship affected with GNAT2 achromatopsia, this family gave a unique opportunity for phenotype-genotype analysis and comparison to other complete achromatopsia subtypes.…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene

Ouechtati

Merdassi²,

Bouyacoub

et al. 2010

J Hum Genet

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Complete achromatopsia is a rare autosomal recessive disease associated with CNGA3, CNGB3, GNAT2 and PDE6C mutations. This retinal disorder is characterized by complete loss of color discrimination due to the absence or alteration of the cones function. The purpose of the present study was the clinical and the genetic characterization of achromatopsia in a large consanguineous Tunisian family. Ophthalmic evaluation included a full clinical examination, color vision testing and electroretinography. Linkage analysis using microsatellite markers flanking CNGA3, CNGB3, GNAT2 and PDE6C genes was performed. Mutations were screened by direct sequencing. A total of 12 individuals were diagnosed with congenital complete achromatopsia. They are members of six nuclear consanguineous families belonging to the same large consanguineous family. Linkage analysis revealed linkage to GNAT2. Mutational screening of GNAT2 revealed three intronic variations c.119À69G4C, c.161+66A4T and c.875À31G4C that co-segregated with a novel mutation p.R313X. An identical GNAT2 haplotype segregating with this mutation was identified, indicating a founder mutation. All patients were homozygous for the p.R313X mutation. This is the first report of the clinical and genetic investigation of complete achromatopsia in North Africa and the largest family with recessive achromatopsia involving GNAT2; thus, providing a unique opportunity for genotype-phenotype correlation for this extremely rare condition.

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“…Both animal and human studies have indicated an essential role of IFN-␥ in protection against mycobacterial infections (19)(20)(21). Despite its role as a bacteriacidal "macrophage activating factor" for other intracellular infections, however, numerous studies have indicated that IFN-␥ does not directly mediate killing of intracellular M. tuberculosis within human phagocytes (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Resident Th1-Like Effector Memory Cells in Pulmonary Recall Responses toMycobacterium tuberculosis

Walrath

Zukowski

Krywiak

et al. 2005

Am J Respir Cell Mol Biol

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We recently described a model of Th1 recall responses based on segmental antigen challenge with purified protein derivative of Mycobacterium tuberculosis (PPD). Bronchoscopic instillation of 0.5 tuberculin units of PPD resulted in localized lymphocytic inflammation in PPD-positive subjects only. Recruited lymphocytes were predominantly CD4ϩ and were enriched for cells capable of PPDspecific interferon (IFN)-␥ production. In the current study, we investigated the mechanisms by which this localized recall response is mobilized. Bronchoscopic PPD challenge of skin test-positive subjects resulted in the production of CXCR3 ligands IFN-␥-inducible protein (IP)-10 and monokine induced by IFN-␥ (Mig), but not of CCR5 ligands macrophage inflammatory protein-1␣ and regulatedupon activation, normal T-cell expressed and secreted, whereas skin test-negative subjects produced none of these chemokines. The great majority of individuals infected with Mycobacterium tuberculosis do not develop active disease, but instead develop specific cell-mediated immunity that is manifest clinically by the development of positive skin-test responses to purified protein derivative of M. tuberculosis (PPD) (1). Skin-test responsiveness is associated with relative protection against subsequent infection with M. tuberculosis (2), although the mechanisms by which this protection is mediated remain poorly understood. We previously sought to establish a model of M. tuberculosis-specific recall responses in the human lung to provide a means to investigate the local responses of immune individuals upon re-exposure to the organism. To do so, we adapted the technique of bronchoscopic segmental antigen challenge that had previously been used extensively to characterize the local Th2-mediated immune responses in the lungs of individuals with atopic asthma using challenge with allergens such as ragweed (3-5). We instead used PPD as the challenge antigen, and compared responses of naturally infected skin test-positive subjects with those of healthy PPD-negative control subjects. A baseline bronchoalveolar lavage (BAL) was performed, followed by administration of 0.5 tuberculin units (TU) of PPD (i.e., 1/10th of the standard skintest dose) into the challenged segment and a control instillation of 10 cc of normal saline into a corresponding segment of the contralateral lung. Repeat BAL of control and challenged segments was performed 48 h later.In our initial studies, we demonstrated that bronchoscopic challenge with PPD resulted in a localized inflammatory response in challenged lung segments of PPD-positive subjects only. Compared with BAL of both baseline and control lung segments of these subjects, PPD-challenged segments displayed a 2.7-fold increase in the total BAL cells and an increase in the percentage of BAL lymphocytes from 10% to 19%. PPDchallenged segments of skin test-positive subjects also displayed an increased percentage of CD4ϩ T cells, and were enriched for cells capable of antigen-specific production of interferon (IFN)-␥ in response to ...

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Clinical and Genetic Heterogeneity of Inherited Autosomal Recessive Susceptibility to DisseminatedMycobacterium bovisBacille Calmette‐Guérin Infection

Cited by 80 publications

References 26 publications

Genetic heterogeneity of megaloblastic anaemia type 1 in Tunisian patients

Genetic heterogeneity of megaloblastic anaemia type 1 in Tunisian patients

Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene

Resident Th1-Like Effector Memory Cells in Pulmonary Recall Responses toMycobacterium tuberculosis

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