Most of human genome is present in two copies (maternal and paternal). However, segments of the genome can be deleted or duplicated, and many of these genomic variations (known as Copy Number ...Variants) are associated with psychiatric disorders. 16p11.2 copy number variants (breakpoint 4–5) confer high risk for neurodevelopmental disorders and are associated with structural brain alterations of large effect-size. Methods used in previous studies were unable to investigate the onset of these alterations and whether they evolve with age. In this study, we aim at characterizing age-related effects of 16p11.2 copy number variants by analyzing a group with a broad age range including younger individuals. A large normative developmental dataset was used to accurately adjust for effects of age. We normalized volumes of segmented brain regions as well as volumes of each voxel defined by tensor-based morphometry. Results show that the total intracranial volumes, the global gray and white matter volumes are respectively higher and lower in deletion and duplication carriers compared to control subjects at 4.5 years of age. These differences remain stable through childhood, adolescence and adulthood until 23 years of age (range: 0.5 to 1.0 Z-score). Voxel-based results are consistent with previous findings in 16p11.2 copy number variant carriers, including increased volume in the calcarine cortex and insula in deletions, compared to controls, with an inverse effect in duplication carriers (1.0 Z-score). All large effect-size voxel-based differences are present at 4.5 years and seem to remain stable until the age of 23. Our results highlight the stability of a neuroimaging endophenotype over 2 decades during which neurodevelopmental symptoms evolve at a rapid pace.
Mucin-1 (MUC1) is a transmembrane glycoprotein that is upregulated upon maturation of dendritic cells (DC) in vitro or in vivo. One of the proposed functions of surface expressed MUC1 is its ...involvement in migration of cells. We hypothesized that MUC1 is involved in DC migration since mature DC (mDC) are highly migratory cells and MUC1 is upregulated on the surface of DC upon maturation. In this study we cultured DC using two maturation cocktails, one cocktail containing IL-4, GM-CSF, TNFα, PGE2, IL-1β and IL-6 (TP1,6-DC) and the other IL-13, GM-CSF, Ribomunyl and IFN-γ (RI-DC). Both maturation cocktails render DC with a similar surface phenotype including CCR7 expression, but only the former induces a migratory capacity of DC to a CCL19 gradient. To analyze the role of surface-expression of MUC1 on TP1,6-DC, that are capable of migration, expression of MUC1 was prevented by adding an anti-MUC1 antibody (Ab) during the maturation process. Compared with matured DC in the absence of the Ab, no difference was observed in chemokine-induced migratory behaviour between the MUC1+ and MUC1− DC populations in a standard Transwell chemotaxis assay, nor in organotypic cultures. Our data clearly demonstrate that surface MUC1 on DC does not influence intrinsic cell-motility, nor is it involved in cell–cell and cell–matrix dependent migration.
The occurrence of mosaic ring chromosome 13 is rare. The mechanism of ring chromosome formation is usually associated with loss of genetic material. We report 2 cases of mosaic ring chromosome 13, ...resulting in deletion of 13qter. The first patient, a 15 year-old boy, presented a delayed psychomotor development, mental retardation, dysmorphic features and bleeding disorders associated with a de novo terminal 13q34 deletion. The second case was a foetus of 31 weeks with prenatal diagnosis of severe malformation such as holoprosencephaly, congenital cardiac defects, gastro-intestinal abnormalities with intrauterine growth retardation, the molecular analysis showed a de novo deletion encompassing the region 13q31.3-q34.
To describe a patient who developed a young-onset, dopa-responsive parkinsonism linked to a de novo heterozygous interstitial duplication 4q.
Case report.
Movement Disorder Outpatient Clinic at the ...University Hospital Centre, Liège, Belgium.
A 31-year-old woman.
Clinical, neuroimaging, and genetic data.
The duplicated region contains 150 known genes, including the α-synuclein (SNCA) gene locus. Motor and 6-(18)Ffluoro-L-dopa positron emission tomography features are similar to those previously reported in heterozygote SNCA duplication carriers. Altered expression of other genes contained in the duplicated region may contribute to clinical features that are uncommon in the phenotypic spectrum of SNCA multiplications such as delayed developmental psychomotor milestones during infancy and musculoskeletal abnormalities.
This case report provides new insights on the genetic basis of parkinsonism.
Epithelial metaplasia (EpM) is an acquired tissue abnormality resulting from the transformation of epithelium into another tissue with a different structure and function. This adaptative process is ...associated with an increased frequency of (pre)cancerous lesions. We propose that EpM is involved in cancer development by altering the expression of adhesion molecules important for cell-mediated antitumor immunity. Langerhans cells (LCs) are intraepithelial dendritic cells that initiate immune responses against viral or tumor antigens on both skin and mucosal surfaces. In the present study, we showed by immunohistology that the density of CD1a(+) LCs is reduced in EpM of the uterine cervix compared with native squamous epithelium and that the low number of LCs observed in EpM correlates with the down-regulation of cell-surface E-cadherin. We also demonstrated that transforming growth factor-beta1 is not only overexpressed in metaplastic tissues but also reduces E-cadherin expression in keratinocytes in vitro by inducing the promoter activity of Slug and Snail transcription factors. Finally, we showed that in vitro-generated LCs adhere poorly to keratinocytes transfected with either Slug or Snail DNA. These data suggest that transforming growth factor-beta1 indirectly reduces antigen-presenting cell density in EpM by affecting E-cadherin expression, which might explain the increased susceptibility of abnormal tissue differentiation to the development of cancer by the establishment of local immunodeficiency responsible for EpM tumorigenesis.
X-linked acrogigantism (X-LAG) syndrome is a newly described form of early onset inheritable pituitary gigantism caused by microduplications on chromosome Xq26.3 including the GPR101 gene. We ...explored the genomic pathophysiology of XLAG syndrome and studied XLAG, pituitary gigantism or acromegaly patients for somatic mosaicism of Xq26.3 microduplications that include GPR101. Copy number variations (CNVs) at the GPR101 gene was assessed and compared to ZIC3 (nearest protein-coding gene on chromosome X not included in duplications causing XLAG) by droplet digital PCR (ddPCR) in 36 acromegalics (24 M; age at diagnosis: 22 - 50 years), 6 acromegaly homogeneous FIPA cases, 22 pituitary gigantism patients, and 20 controls. In 18 XLAG patients (6 M-3 sporadic, 3 familial, and 12 F - 11 sporadic, 1 familial) high-definition array comparative genomic hybridization (HD-aCGH) and breakpoint junction (JCT)-specifc ddPCR were performed to characterize Xq26.3 duplications and quantify their level of mosaicism. On HD-aCGH all XLAG micoduplications were unique and included GPR101. All male subjects had a decreased log2 ratio (LR) than expected value of LR = 1, suggesting potential mosaicism, whereas there was no evidence of mosaicism in XLAG females. Males as a group had significantly lower LR values compared with female patients. Moreover, sporadic males had lower levels of Xq26.3duplication mosaicism in blood DNA (ranged 16.1-53.8%) than familial XLAG males (69.1-78.5%). These findings were then confirmed using a personalized (JCT)-specific quantification ddPCR and the mosaicism levels obtained with this technique were consistent with the HD-aCGH results. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG cases in acromegaly/gigantism patients' population by abnormalities in copy number at GPR101 vs. ZIC3. One female gigantism patient was found having increased CNV threshold for GPR101 and was subsequently diagnosed with XLAG microduplication on HD-aCGH. In this study we demonstrated using a combination of HD-aCGH and novel ddPCR approaches, for the first time, that XLAG syndrome can be caused by somatic mosaicism for duplications at chromosome Xq26.3. Sporadic males but not females with XLAG were found to have variable degrees of somatic mosaicism. Screening for changes in CNV at GPR101 by ddPCR technique may identify a potential XLAG cases among pituitary gigantism population.
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