Pierre-Marie Sinet

Molecular mapping of twenty-four features of Down syndrome on chromosome 21.

To determine which regions of chromosome 21 are involved in the pathogenesis of specific features of Down syndrome, we analysed, phenotypically and molecularly, 10 patients with partial trisomy 21. Six minimal regions for 24 features were defined by genotype-phenotype correlations. Nineteen of these features could be assigned to just 2 regions: short stature, joint hyperlaxity, hypotonia, major contribution to mental retardation and 9 anomalies of the face, hand and foot to the region D21S55, or Down syndrome chromosome region (DCR), located on q22.2 or very proximal q22.3, and spanning 0.4–3 Mb; 6 facial and dermatoglyphic anomalies to the region D21S55-MX1, including the DCR and spanning a maximum of 6 Mb on q22.2 and part of q22.3. Thus, the complex phenotype that constitutes Down syndrome may in large part simply result from the overdosage of only one or a few genes within the DCR and/or region D21S55-MX1.

Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21

Down syndrome (DS) is one of the most frequent congenital birth defects, and the most common genetic cause of mental retardation. In most cases, DS results from the presence of an extra copy of chromosome 21. DS has a complex phenotype, and a major goal of DS research is to identify genotype–phenotype correlations. Cases of partial trisomy 21 and other HSA21 rearrangements associated with DS features could identify genomic regions associated with specific phenotypes. We have developed a BAC array spanning HSA21q and used array comparative genome hybridization (aCGH) to enable high-resolution mapping of pathogenic partial aneuploidies and unbalanced translocations involving HSA21. We report the identification and mapping of 30 pathogenic chromosomal aberrations of HSA21 consisting of 19 partial trisomies and 11 partial monosomies for different segments of HSA21. The breakpoints have been mapped to within ∼85 kb. The majority of the breakpoints (26 of 30) for the partial aneuploidies map within a 10-Mb region. Our data argue against a single DS critical region. We identify susceptibility regions for 25 phenotypes for DS and 27 regions for monosomy 21. However, most of these regions are still broad, and more cases are needed to narrow down the phenotypic maps to a reasonable number of candidate genomic elements per phenotype.

beta. amyloid gene duplication in Alzheimer's disease and karyotypically normal Down syndrome

With the recently cloned complementary DNA probe, lambda Am4 for the chromosome 21 gene encoding brain amyloid polypeptide (beta amyloid protein) of Alzheimers disease, leukocyte DNA from three patients with sporadic Alzheimers disease and two patients with karyotypically normal Down syndrome was found to contain three copies of this gene. Because a small region of chromosome 21 containing the ets-2 gene is duplicated in patients with Alzheimers disease, as well as in karyotypically normal Down syndrome, duplication of a subsection of the critical segment of chromosome 21 that is duplicated in Down syndrome may be the genetic defect in Alzheimers disease.

Age-related changes in antioxidant enzymes and lipid peroxidation in brains of control and transgenic mice overexpressing copper-zinc superoxide dismutase

The aim of our study was first to obtain a comprehensive profile of the brain antioxidant defense potential and peroxidative damage during aging. We investigated copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD), seleno-dependent glutathione peroxidase (GSH-PX), glutathione reductase (GSSG-R) activities, endogenous and in vitro stimulated lipid peroxidation in 40 brains of control mice divided into 3 age groups: 2 months (young), 12 months (middle-aged) and 28 months (old). We found a positive correlation between age and activities of CuZnSOD (r = 0.47; P < 0.01) and GSH-PX (r = 0.72; P < 0.0001). CuZnSOD and GSH-PX activities are independently regulated during brain aging since temporal changes of these two enzymes do not correlate. No modification in MnSOD activity and basal lipid peroxidation was observed as a function of age. Nevertheless, stimulated lipid peroxidation was significantly higher at 12 months (6.53 +/- 0.71 mumole MDA/g tissue) than at 2 months (5.69 +/- 0.90) and significantly lower at 28 months (5.13 +/- 0.33) than at 12 months. Second, we used genetic manipulations to construct transgenic mice that specifically overexpress CuZnSOD to understand the role of CuZnSOD in neuronal aging. The human CuZnSOD transgene expression was stable during aging. The increased CuZnSOD activity in the brain (1.9-fold) of transgenic mice resulted in an enhanced rate of basal lipid peroxidation and in increased MnSOD activity in the 3 age groups. Other antioxidant enzymes did not exhibit modifications indicating the independence of the regulation between CuZnSOD and glutathione-related enzymes probably due to their different cellular localization in the brain.

Trisomie 21 et superoxyde dismutase-1 (IPO-A): Tentative de localisation sur la sous bande 21 q 22.1☆

Abstract The enzymatic activity of SOD-1 in erythrocytes has been studied in several cases of partial monosomies and full and partial trisomies 21. The following results are obtained: 1. The excess of SOD-1 activity in the case of the regular trisomy 21 is confirmed. 2. In monosomy 21 p ter→21 q 21, the enzymatic activity is normal. 3. In trisomy 21 p ter→21 q 21, the enzymatic activity is equally normal. 4. In trisomy 21 q 22, and more precisely in trisomy 21 q 22.1, the activity is increased. Consequently, the SOD-1 gene locus, previously assigned to chromosome 21, is very likely localised in sub-band 21 q 22.1. Finally, the phenotypic analysis indicates that the trisomy of this sub-band is responsible for a great part of the clinical features of trisomy for the whole chromosome 21. The possible role of the SOD-1 excess in the pathogeny of trisomy 21 is discussed.

Neuronal-specific expression of human copper-zinc superoxide dismutase gene in transgenic mice: animal model of gene dosage effects in Down's syndrome

It has been suggested that copper-zinc superoxide dismutase (CuZn SOD) increment, by accelerating hydrogen peroxide formation, might promote oxidative damage within trisomy 21 cells and might be involved in the various neurobiological abnormalities found in Downs syndrome such as premature aging and Alzheimer-type neurological lesions. In order to test this hypothesis, we have developed strains of transgenic mice carrying the human CuZn SOD gene. The human transgene expression resulted in increased CuZn SOD activity predominantly in the brain (1.93 fold). Immunohistochemical and in situ hybridization analysis of brain sections revealed that human CuZn SOD protein and mRNA was preferentially expressed in neurons, particularly in pyramidal cells of Ammons horn and granule cells of gyrus dentate. The amount of thiobarbituric acid (TBA)-reactive material was significantly higher in transgenic brains compared to controls, strongly suggesting an increased level of peroxidation in vivo. These results support the notion that CuZn SOD gene dosage effect could play a role in the pathogenesis of rapid aging features in the brain of Downs syndrome patients.

Increase in glutathione peroxidase activity in erythrocytes from trisomy 21 subjects

Glutathione peroxidase activity has been measured in erythrocytes from normal subjects and from trisomy 21 patients. The latter cases show about 50 % increase of this enzyme similar to the increase observed for superoxide dismutase (erythrocuprein) suggesting either localisation of the gene for glutathione peroxidase on chromosome 21 (as is the case for erythrocuprein) or regulation of this enzyme by intracellular levels of O2•, H2O2 or superoxide dismutase.

Trisomy 21 (Down's Syndrome) glutathione peroxidase, hexose monophosphate shunt and I.Q.

Abstract Glutathione peroxidase activity is increased in erythrocytes and fibroblasts from trisomy 21 patients. Hexose monophosphate shunt activity in erythrocytes is also increased. The enzymatic changes may be secondary to accelerated oxidative processes within cells, which would be in accord with some of the clinical features of Downs Syndrome. A highly positive correlation exists between erythrocyte glutathione peroxidase and I.Q. This latter finding may indicate an important role for glutathione peroxidase in the cerebral status of these patients.

Preferential localization of copper zinc superoxide dismutase in the vulnerable cortical neurons in Alzheimer's disease

The distribution of cells containing CuZn superoxide dismutase (CuZn SOD) was determined in hippocampi and associative cortex from normal and Alzheimers individuals by using antisera against native and denatured CuZn SOD proteins. Immunostaining was intense in large pyramidal neurons, moderate in hippocampal granule cells and very weak in other cells. In the hippocampus of an Alzheimers patient, successive immunostaining of the same tissue section by anti CuZn SOD and anti paired helical filaments antisera show that both normal and degenerating cells are labelled by the anti CuZn SOD antiserum. Thus, large pyramidal neurons which are potentially susceptible to degenerative processes in AD have the property to contain higher amounts of CuZn SOD than other brain cells.

Superoxide dismutase activities of blood platelets in trisomy 21

Abstract Mitochondrial and cytoplasmic superoxide dismutase activities have been determined in blood platelets from normal subjects and from trisomy 21 patients. The cytoplasmic enzyme (erythrocuprein) shows the same increase of 50 % in trisomy 21 compared with controls, previously noted in erythrocytes, whereas the mitochondrial manganese containing enzyme is significantly decreased by one third in platelets from cases of trisomy 21. The biological significance of these results is discussed.