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International audience; The nucleoredoxin gene NXNL2 encodes for two products through alternative splicing, rod-derived cone viability factor-2 (RdCVF2) that mediates neuronal survival and the thioredoxin-related protein (RdCVF2L), an enzyme that regulates the phosphorylation of TAU. To investigate the link between NXNL2 and tauopathies, we studied the Nxnl2 knockout mouse (Nxnl2−/−). We established the expression pattern of the Nxnl2 gene in the brain using a Nxnl2 reporter mouse line, and characterized the behavior of the Nxnl2−/− mouse at 2 months of age. Additionally, long term potentiation and metabolomic from hippocampal specimens were collected at 2 months of age. We studied TAU oligomerization, phosphorylation and aggregation in Nxnl2−/− brain at 18 months of age. Finally, newborn Nxnl2−/− mice were treated with adeno-associated viral vectors encoding for RdCVF2, RdCVF2L or both and measured the effect of this therapy on long-term potential, glucose metabolism and late-onset tauopathy. Nxnl2−/− mice at 2 months of age showed severe behavioral deficiency in fear, pain sensitivity, coordination, learning and memory. The Nxnl2−/− also showed deficits in long-term potentiation, demonstrating that the Nxnl2 gene is involved in regulating brain functions. Dual delivery of RdCVF2 and RdCVF2L in newborn Nxnl2−/− mice fully correct long-term potentiation through their synergistic action. The expression pattern of the Nxnl2 gene in the brain shows a predominant expression in circumventricular organs, such as the area postrema. Glucose metabolism of the hippocampus of Nxnl2−/− mice at 2 months of age was reduced, and was not corrected by gene therapy. At 18-month-old Nxnl2−/− mice showed brain stigmas of tauopathy, such as oligomerization, phosphorylation and aggregation of TAU. This late-onset tauopathy can be prevented, albeit with modest efficacy, by recombinant AAVs administrated to newborn mice. The Nxnl2−/− mice have memory dysfunction at 2-months that resembles mild-cognitive impairment and at 18-months exhibit tauopathy, resembling to the progression of Alzheimer's disease. We propose the Nxnl2−/− mouse is a model to study multistage aged related neurodegenerative diseases. The NXNL2 metabolic and redox signaling is a new area of therapeutic research in neurodegenerative diseases.

Objectives Consanguinity is common in Tunisia. However, little information exists on its impact on recessive disorders. In this study, we evaluate the impact of consanguineous marriages on the occurrence of some specific autosomal recessive disorders and consider how other factors, such as population substructure and mutation frequency, may be of equal importance in disease prevalence. Methods Consanguinity profiles were retrospectively studied among 425 Tunisian patients suffering from autosomal recessive xeroderma pigmentosum, dystrophic epidermolysis bullosa, nonsyndromic retinitis pigmentosa, Gaucher disease, Fanconi anemia, glycogenosis type I, and ichthyosis, and compared to those of a healthy control sample. Results Consanguinity was observed in 341 cases (64.94%). Consanguinity rates per disease were 75.63, 63.64, 60.64, 61.29, 57.89, 73.33, and 51.28%, respectively. First-cousin marriages were the most common form of consanguinity (48.94%) with the percentages of 55.46, 45.46, 47.87, 48.39, 45.61, 56.66, and 35.90%, respectively. A very high level of geographic endogamy was also observed (93.92%), with the values by disease ranging between 75.86 and 96.64%. We observed an overall excess risk associated to consanguinity of nearly sevenfold which was proportional to the number of affected siblings and the frequency of disease allele in the family. Consanguinity was significantly associated with the first five cited diseases (odds ratio = 24.41, 15.17, 7.5, 5.53, and 5.07, respectively). However, no meaningful effects were reported among the remaining diseases. Conclusions This study reveals a variation in the excess risk linked to consanguinity according to the type of disorder, suggesting the potential of cryptic population substructure to contribute to disease incidence in populations with complex social structure like Tunisia. It also emphasizes the role of other health and demographic aspects such as mutation frequency and reproductive replacement in diseases etiology. Am. J. Hum. Biol., 2015. © 2015 Wiley Periodicals, Inc.

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.119-69G > C, c.161+66A > T and c.875 31G > C 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. Journal of Human Genetics (2011) 56, 22-28; doi:10.1038/jhg.2010.128; published online 25 November 2010

Purpose To describe the phenotypic characteristics of seven families with childhood onset retinal dystrophy in Northeastern Tunisia and to determine the linkage with RPE65 gene mutation. Methods Seventy subjects were concerned (18 affected patients and 52 unaffected). Ophthalmic examinations included visual function testing, fundus examination, full field ERG, spectral OCT and fluoroangiography. After patients consent, screening of RPE65 gene was performed by bi-directional sequencing. Results All affected members had a severe retinal dystrophy with history of low visual acuity since infancy. The age at first ophthalmic examination ranged from 5 to 55 years old. Visual acuity ranged from no light perception to 2/10. Two retinal patterns were identified: the first one presented midperipheral white dot deposits, whereas the second showed midperipheral pigmented clumps without any white deposits. Atrophic and /or pigmentary macular changes were present in most patients. Mutational screening of the RPE65 gene identified an homozygous R91W mutation co-segregating with the disease in 11 affected individuals. Two siblings were compound heterozygous for this mutation. Conclusion We identified and characterized an endemic form of early onset rod-cone dystrophy in a consanguineous population from northeastern Tunisia, due to the prevalence of a single single homozygous missense R91W mutation in exon 4 of the RPE65 gene. This could have practical value for genetic screening strategy in young affected tunisian patients.

Introduction Mal de Meleda is a rare form of palmoplantar keratoderma, with autosomal recessive transmission. It is characterized by diffuse erythema and hyperkeratosis of the palms and soles. Recently, mutations in the ARS (component B) gene (ARS, MIM: 606119) on chromosome 8q24.3 have been identified in families with this disorder. Congenital cataract is a visual disease that may interfere with sharp imaging of the retina. Mutations in the heat-shock transcription factor 4 gene (HSF4; MIM: 602438) may result in both autosomal dominant and autosomal recessive congenital cataracts. Case presentation A Tunisian family with two female siblings aged 45 and 30 years, presented with a clinical association of mal de Meleda and congenital cataract. The two patients exhibited diffuse palmoplantar keratodermas. One of them presented with a total posterior subcapsular cataract and had a best corrected visual acuity at 1/20 in the left eye and with the right eye was only able to count fingers at a distance of one foot. The other woman had a slight posterior subcapsular lenticular opacity and her best corrected visual acuity was 8/10 in the right eye and with her left eye she was only able to count fingers at a distance of one foot. A mutational analysis of their ARS gene revealed the presence of the homozygous missense mutation C99Y and two single nucleotide polymorphisms (-55G>C and -60G>C). The splice mutation (c.1327+4A-G) within intron 12 of the HSF4 gene, which has been previously described in Tunisian families with congenital cataract, was not found in the two probands within this family. Conclusion To the best of our knowledge, such original clinical association has not been reported previously. The association of these two autosomal recessive diseases might have occurred in this family due to a high degree of inbreeding. The C99Y mutation may be specific to the Tunisian population as it has been exclusively reported so far in only three Tunisian families with mal de Meleda.

Central areolar choroidal dystrophy (CACD) is a rare inherited disease, which causes progressive profound loss of vision in patients during their fourth decade. It is characterized by atrophy of retinal pigment epithelium, photoreceptors and choriocapillaris. The disease showed a genetic heterogeneity. Previously, mutations in the peripherin/RDS gene and a linkage to the CACD locus in the 17p13 region have been reported in CACD families. In this study, we report on a clinical and genetic investigation of CACD in a large Tunisian consanguineous family with 21 affected individuals in three living generations. CACD has been associated with drusen in some of them. Linkage analysis and mutational screening exclude linkage to the PRPH2/RDS gene and to the CACD locus. These data provide further evidence of the genetic heterogeneity of CACD.

International audience; Hereditary multiple exostoses (HME) is an autosomal dominant orthopaedic disorder most frequently caused by mutations in the EXT1 gene. The aim of the present study is to determine the underlying molecular defect of HME in two multigenerational Tunisian families with 21 affected members and to examine the degree of intrafamilial variability. Linkage analysis was performed using three microsatellite markers encompassing the EXT1 locus and mutation screening was carried out by direct sequencing. In family 1, evidence for linkage to EXT1 was obtained on the basis of a maximum LOD score of 4.26 at theta = 0.00 with D8S1694 marker. Sequencing of the EXT1 revealed a heterozygous G > T transversion (c.1019G > T) in exon 2, leading to a missense mutation at the codon 340 (p.Arg340Leu). In family 2 we identified a novel heterozygous 1 bp deletion in the exon 1 (c.529\₅31delA) leading to a premature codon stop and truncated EXT1 protein expression (p.Lys177LysfsX15). This mutation was associated with the evidence of an intrafamilial clinical variability and considered to be a novel disease-causing mutation in the EXT1 gene. These findings provide additional support for the involvement of EXT1 gene in the HME disease.

Background Atrial septal defect (ASD) is an autosomal dominant disease characterized by left-to-right shunting and increased right ventricular output. Approximately 5–10% of congenital heart diseases (CHD) are due to ASD, which is one of the most frequent CHD found in adults. The gene responsible for ASD was mapped to chromosome 5q35 encoding the transcription factor NKX2–5 that plays an important role for the regulation of septation during cardiac morphogenesis. Methods A Tunisian family including four affected members was investigated. Individuals were genotyped using the polymorphic microsatellite markers D5S394 and D5S2069 overlapping the NKX2–5 gene. Results We report here clinical and molecular investigation of a Tunisian consanguineous family with four affected members. Two presented with ASD associated with prolonged PR interval, whereas the other two presented only a prolonged PR interval. We also identified five asymptomatic individuals in the same family with ventricular preexcitation. Although the patients were products of a consanguineous marriage, no other abnormalities were observed in this family. Genotyping and linkage analysis showed exclusion of linkage between the gene responsible for ASD in this family and NKX2.5 gene. Conclusions Our results further confirm the genetic heterogeneity of ASD.

Introduction La retinopathie pigmentaire (RP) est caracterisee par sa triple heterogeneite : clinique, genetique et moleculaire. Le but du travail est de degager les principales caracteristiques cliniques et genetiques des RP. Materiels et Methodes Il s’agit d’une retrospective portant sur 36 patients issus de 9 familles originaires de la region du Cap-Bon (Tunisie), atteinte des RP non syndromique. Tous nos patients ont beneficie d’un examen ophtalmologique et general complete par des explorations para-cliniques et d’une etude genetique. Discussion Nos resultats cliniques ont revele une grande heterogeneite. En effet, trois formes cliniques en fonction de l’âge de debut ont ete retrouvees : la RP de la premiere enfance, la RP a debut precoce et la RP classique. Trois formes cliniques en fonction des donnees du FO ont egalement ete identifiees : RP a spicules, retinopathie ponctuee albescente et RP avec mottes pigmentaires. Les complications a type de cataracte et d’œdeme maculaire cystoide etaient presentes, dans respectivement 52 % et 11 % des cas. L’analyse des arbres genealogiques a conclu a un mode de transmission autosomique recessif dans 8 familles et autosomique dominant dans une famille. L’etude moleculaire (analyse de liaison genetique et sequencage de l’ADN) a mis en evidence la mutation R91W sur le gene RPE65 chez tous les individus atteints appartenant a deux familles avec phenotype de RP de la premiere enfance et avec au FO des mottes pigmentaires, suggerant ainsi une correlation phenotype-genotype. Les genes RHO, RDS, ABCA4 et ROM1 ont ete exclus. Conclusion Dans la majorite des RP, on ne retrouve pas de correlation phenotypegenotype evidente, ce qui ne facilite pas la caracterisation du defaut moleculaire responsable de ces pathologies. Toutefois, devant tout patient atteint de RP et rapportant une histoire familiale d’hesperanopie, une enquete genetique et moleculaire s’impose en vue de therapie future.

Introduction La maladie de Stargardt est la plus frequente des heredo-degenerescences maculaires et peut se manifester sous differentes formes cliniques. Il s’agit le plus souvent d’une transmission autosomique recessive par mutation du gene ABCA4 qui code pour une proteine ABCR. Nous rapportons le cas d’une famille tunisienne consanguine dont certains membres presentent des phenotypes Stargardt-like differents. L’atteinte semble etre transmise sur le mode autosomique recessif. Une analyse genetique a ete realisee a la recherche d’une eventuelle correlation genotype-phenotype. Materiels et Methodes Cette etude a concerne deux familles nucleaires consanguines chez lesquelles nous avons retrouve sept sujets atteints. Tous les membres ont beneficie d’un examen ophtalmologique : acuite visuelle, champ visuel, fond d’œil, angiographie retinienne a la fluoresceine et electroretinogramme. Un genotypage a ete realise utilisant les microsatellites D1S2813 et D1S2849 pour le gene ABCA4 et un autre marqueur intragenique. Une recherche des mutations deja connues a ete realisee par micropuce du gene ABCA4 pour un patient et par sequencage ciblant huit exons pour les autres. Resultats Sur le plan clinique, trois phenotypes differents ont ete individualises : un phenotype de Stargardt avec maculopathie et silence choroidien pour une patiente, un phenotype de Stargardt-fundus flavimaculatus pour quatre patients et un phenotype pouvant correspondre a un Stargardt evolue ou a une cone rod dystrophy avec une atrophie generalisee de la retine pour deux patients. L’analyse genetique a demontre l’implication d’une mutation du gene ABCA4 dans l’apparition de la maladie et il existe chez les patients atteints trois individus recombinants. La mutation Arg 681Ter a ete retrouvee a l’etat heterozygote dans une des branches familiales. Aucune des mutations connues du gene n’a ete retrouvee chez les autres membres atteints de la famille. Discussion Ceci suggere la presence de mutations genetiques differentes au niveau du gene ABCA4. Conclusion Dans le present travail, nous rapportons une large genealogie presentant une dystrophie retinienne liee au gene ABCA4. Bien que cette famille soit fortement consanguine et qu’une seule entite genetique semble etre impliquee, elle presente une forte heterogeneite phenotypique due probablement a une heterogeneite mutationnelle.