Shedding of proangiogenic microvesicles from hypertrophic scar myofibroblasts

Hypertrophic scars are a common complication of burn injuries and represent a major challenge in terms of prevention and treatment. These scars are characterized by a supraphysiological vascular density and by the presence of pathological myofibroblasts (Hmyos) displaying a low apoptosis propensity. However, the nature of the association between these two hallmarks of hypertrophic scarring remains largely unexplored. Here, we show that Hmyos produce signalling entities known as microvesicles that significantly increase the three cellular processes underlying blood vessel formation: endothelial cell proliferation, migration and assembly into capillary‐like structures. The release of microvesicles from Hmyos was dose‐dependently induced by the serum protein α‐2‐macroglobulin. Using flow cytometry, we revealed the presence of the α‐2‐macroglobulin receptor—low‐density lipoprotein receptor‐related protein 1—on the surface of Hmyos. The inhibition of the binding of α‐2‐macroglobulin to its receptor abolished the shedding of proangiogenic microvesicles from Hmyos. These findings suggest that the production of microvesicles by Hmyos contributes to the excessive vascularization of hypertrophic scars. α‐2‐Macroglobulin modulates the release of these microvesicles through interaction with low‐density lipoprotein receptor‐related protein 1.     

Estimation of Recent and Ancient Inbreeding in a Small Endogamous Tunisian Community Through Genomic Runs of Homozygosity

Runs of homozygosity (ROHs) are extended genomic regions of homozygous genotypes that record populations’ mating patterns in the past. We performed microarray genotyping on 15 individuals from a small isolated Tunisian community. We estimated the individual and population genome‐wide level of homozygosity from data on ROH above 0.5 Mb in length. We found a high average number of ROH per individual (48.2). The smallest ROH category (0.5–1.49 Mb) represents 0.93% of the whole genome, while medium‐size (1.5‐4.99 Mb) and long‐size ROH (≥5 Mb) cover 1.18% and 0.95%, respectively. We found that genealogical individual inbreeding coefficients (F_ped) based on three‐ to four‐generation pedigrees are not reliable indicators of the current proportion of genome‐wide homozygosity inferred from ROH (F_ROH) either for 0.5 or 1.5 Mb ROH length thresholds, while identity‐by‐descent sharing is a function of shared coancestry. This study emphasizes the effect of reproductive isolation and a prolonged practice of consanguinity that limits the genetic heterogeneity. It also provides evidence of both recent and ancient parental relatedness contribution to the current level of genome‐wide homozygosity in the studied population. These findings may be useful for evaluation of long‐term effects of inbreeding on human health and for future applications of ROHs in identifying recessive susceptibility genes.     

First case report of Cohen syndrome in the Tunisian population caused by <Emphasis Type="Italic">VPS13B</Emphasis> mutations

Background

Cohen syndrome is a rare autosomal recessive developmental disorder that comprises variable clinical features counting developmental delay, pigmentary retinopathy, myopia, acquired microcephaly, truncal obesity, joint hypermobility, friendly disposition and intermittent neutropenia. VPS13B (vacuolar protein sorting 13, yeast, homologue of B) gene is the only gene responsible for Cohen Syndrome, causative mutations include nonsense, missense, indel and splice-site variants. The integrity of the Golgi apparatus requires the presence of the peripheral membrane protein VPS13B that have an essential function in intracellular protein transport and vesicle-mediated sorting.

Case presentation

In this study, we performed whole exome sequencing (WES) in a Tunisian family with two young cases having developmental delay, hypotonia, autism spectrum disorder, ptosis and thick hair and eyebrows. The proposita presented also pigmentory retinopathy. Compound heterozygous mutation in VPS13B gene was detected by WES. This mutation inherited from healthy heterozygous parents, supports an unpredictable clinical diagnosis of Cohen Syndrome. The proband’s phenotype is explained by the presence of compound heterozygous mutations in the VPS13B gene. This finding refined the understanding of genotype-phenotype correlation.

Conclusions

This is the first report of a Tunisian family with Cohen syndrome mutated in the VPS13B gene.

     

Non alcoholic steatohepatitis: a multifactorial,frequent, paucysymptomatic liver disease with a fibrotic outcome

BACKGROUND: The aim of this study was to evaluate the morphological, clinical and biochemical characteristics of non alcoholic steatohepatitis to understand its pathogenesis.PATIENTS AND METHODS: From January 1993 to June 2000, 44 patients were selected on histological criteria. Alcohol intake, blood pressure, weight, glycaemia, lipid, immune, iron profiles hemochromatosis (HFE) gene mutations were analyzed. Patients were re-examined thereafter or in June 2000.RESULTS: Twenty one women and 10 men were included (mean age=54). Nineteen patients were asymptomatic (61.3%). Patients often presented with an increase in alanine aminotransferase. This was correlated with steatosis (P=0.008). Hypertension, excess weight, abnormal serum glucose levels and dyslipidaemia were respectively observed in 10 (32.2%), 24 (77.4%), 16 (51.6%) and 18 (58.1%) patients. Thirteen of these patients (41.9%) presented abnormal autoantibodies titers without autoimmune hepatitis; 18 (58.1%) presented an iron overload. A mutation of the HFE gene was detected in 14 of 25 patients (51.6%). Liver iron concentrations were not correlated to the extent of fibrosis extension or with mutations.CONCLUSION: Increased alanine aminotransferase levels usually revealed non alcoholic steatohepatitis. A high prevalence of autoantibodies, iron overload and mutation of the HFE gene were detected. Non alcoholic steatohepatitis should be diagnosed because it can be associated with cirrhosis.