Biomedical subjects

Jean Morissette

Publications and source records attributed to Jean Morissette.

10 recordsLinked to original sources

PubMed2006

Dehydroepiandrosterone (DHEA) is an anabolic steroid like dihydrotestosterone (DHT), the most potent natural androgen, and tetrahydrogestrinone (THG).

We have recently taken advantage of the unique power of DNA microarrays to compare the genomic expression profile of tetrahydrogestrinone (THG) with that of dihydrotestosterone (DHT), the most potent natural androgen, thus clearly demonstrating that THG is an anabolic steroid. In 2004, the U.S. Controlled Substances Act has been modified to include androstenedione (4-dione) as an anabolic steroid. However, despite the common knowledge that dehydroepiandrosterone (DHEA) is the precursor of testosterone, DHEA has been excluded from the list of anabolic steroids. We thus used the same DNA microarray technology to analyze the expression profile of practically all the 30,000 genes of the mouse genome modulated by DHEA and DHT in classical androgen-sensitive tissues. Daily subcutaneous injections of DHT (0.1mg) or DHEA (3mg) for 1 month in gonadectomized C57BL6/129 SV mice increased ventral prostate, dorsal prostate, seminal vesicle and preputial gland weight (p<0.01 for all tissues). As early as 24h after single injection of the two steroids, 878, 2681 and 14 probe sets were commonly stimulated or inhibited (p<0.01, change> or =30%), in the prostate (ventral+dorsal), seminal vesicles and preputial glands, respectively, compared to tissues from gonadectomized control animals. After 7 days of daily treatment with DHEA and DHT, 629, 919 and 562 probe sets were commonly modulated in the same tissues while after 27 days of treatment, 1195, 5127 and 2883 probe sets were modulated, respectively. In analogy with the data obtained with THG, the present microarray data provide an extremely precise and unquestionable genomic signature and proof of the androgenic/anabolic activity of DHEA. Such data add to the literature showing that DHEA is transformed into androgens in the human peripheral tissues as well as in laboratory animal species, including the monkey, thus exerting potent androgenic/anabolic activity. The present microarray approach to identify anabolic compounds is applicable to all potential androgenic/anabolic compounds.

Anabolic Agents↗

PubMed2006

Sequestosome 1: mutation frequencies, haplotypes, and phenotypes in familial Paget's disease of bone.

UNLABELLED: Mutations of the SQSTM1/p62 gene are commonly observed in PDB. Screening an updated sample from Quebec and using previously published data from other populations, we compared frequency estimates for SQSTM1/p62 mutations and haplotype distribution. The P392L mutation was the most prevalent, embedded in two different haplotypes, possibly shared by other populations. We also examined the phenotype and penetrance of P392L. INTRODUCTION: There is accumulating evidence that supports a contribution of genetic factors in the etiology of Paget's disease of bone (PDB), and several genetic loci have been suggested for the disorder. The sequestosome1/p62 (SQSTM1/p62) gene was the first gene identified to have a role in PDB, with 14 mutations reported to date. MATERIAL AND METHODS: To evaluate the importance of the SQSTM1/p62 mutations in PDB, we recruited, sequenced, and genotyped a total of 123 carriers from 20 families in addition to 214 unrelated PDB patients. We compared the frequency of SQSTM1/p62 mutations in familial and unrelated cases among different populations. Finally, we examined the phenotypic expression and penetrance of the P392L mutation in the Quebecois families. RESULTS AND CONCLUSIONS: The 14 mutations reported in SQSTM1/p62 all affect the ubiquitin-associated domain of the protein. The P392L mutation is the most commonly observed mutation in PDB patients and was consistently found in unrelated and familial PDB cases in the populations tested. Analysis of adjacent polymorphisms suggests that P392L is associated with two different haplotypes in the Quebecois patients, similar to what has been observed in European populations. In Quebec, both haplotypes had similar frequencies in unrelated P392L carriers, whereas one haplotype was predominant in the other populations studied. These data suggest that these two haplotypes, possibly introduced by European founders in the Quebecois population, were equally distributed in the succeeding generations. Finally, the P392L mutation is transmitted as an autosomal dominant trait in the Quebecois families, with a high but incomplete penetrance peaking after age 60. The large phenotypic variability and similarity between unrelated and familial cases, respectively, remain unexplained and require further research.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Tetrahydrogestrinone induces a genomic signature typical of a potent anabolic steroid.

Tetrahydrogestrinone (THG) is a recently identified compound having the greatest impact in the world of sports. In order to obtain a highly accurate and sensitive assessment of the potential anabolic/androgenic activity of THG, we have used microarrays to identify its effect on the expression of practically all the 30,000 genes in the mouse genome and compared it with the effect of dihydrotestosterone (DHT), the most potent natural androgen. Quite remarkably, we found that 671 of the genes modulated by THG in the mouse muscle levator ani are modulated in a similar fashion by DHT, while in the gastrocnemius muscle and prostate, 95 and 939 genes respectively, are modulated in common by the two steroids. On the other hand, THG is more potent than DHT in binding to the androgen receptor, while, under in vivo conditions, THG possesses 20% of the potency of DHT in stimulating prostate, seminal vesicle and levator ani muscle weight in the mouse. The present microarray data provide an extremely precise and unquestionable signature of the androgenic/anabolic activity of THG, an approach which should apply to the analysis of the activity of any anabolic steroid.

Anabolic Agents↗

PubMed2004

Axenfeld-Rieger anomaly: a novel mutation in the forkhead box C1 (FOXC1) gene in a 4-generation family.

OBJECTIVE: To characterize DNA mutations in a pedigree of Axenfeld-Rieger anomaly (ARA) (Online Mendelian Inheritance of Man 601631), a clinically and genetically heterogeneous, autosomal dominantly inherited disorder associated with anterior chamber abnormalities and glaucoma. DESIGN: Observational case-control and DNA linkage and screening studies. PARTICIPANTS: Affected (10 cases) and unaffected (5 controls) members of a family with ARA. METHODS: Clinical characteristics of ARA were documented by history or physical examination of symptomatic individuals. With their informed consent, a blood sample was collected from each of 10 affected and 5 unaffected family members. DNA was tested for linkage to the IRID1 locus at chromosome 6p25, a known locus for ARA/Rieger syndrome. A candidate gene previously mapped at this locus, FOXC1, was screened for mutations in cases and controls. Main Outcome Measure Linkage of the ARA phenotype at the 6p25 locus and mutation detected in FOXC1. RESULTS: Direct sequencing of FOXC1 detected a new mutation, T272C, that segregated with the ARA phenotype in this family and was not detected in DNA from family members without ARA. This mutation, a T-->C transition, is predicted to result in a change of isoleucine to threonine (Ile9lThr) in a highly conserved location within the first helix of the forkhead domain. CONCLUSION: Characterization of the FOXC1 mutation in family members with ARA furthers our understanding of the molecular origin of developmental glaucoma and other anterior segment disorders.

Adult↗

PubMed2004

Adipose tissue transcriptome by serial analysis of gene expression.

OBJECTIVE: To describe the genomic expression profile or transcriptome of adipose tissue using the serial analysis of gene expression method. RESEARCH METHODS AND PROCEDURES: The serial analysis of gene expression strategy is based on isolation of short sequences (tags), which usually correspond to unique transcripts, and on their concatenation into long DNA molecules, which are then cloned and sequenced. Experiments were performed with mRNA from retroperitoneal adipose tissue of male C57BL6 mice. RESULTS: We isolated 45,996 tags corresponding to more than 17,000 different genes. Eighty-eight genes were expressed at more than 0.1% of the total population and represented 26% of the mRNA population identified. The most expressed genes were: carbonic anhydrase 3 (1.97%), cytochrome c oxidase (COX) 1 (1.47%), COX2 (1.25%), diazepam binding inhibitor (1.04%), a novel transcript (0.87%), COX3 (0.55%), fatty acid-binding protein 4 (0.55%), and NADH dehydrogenase 4 (0.52%). Other genes known to be expressed in adipose tissue, such as uncoupling protein 2, angiotensinogen, adipsin, and insulin-like growth factor 1, were found at a lower level. Several tags corresponding to novel transcripts were also found. DISCUSSION: To our knowledge, the present results provide for the first time a quantitative description of the transcriptome in adipose tissue.

Adipose Tissue↗

PubMed2004

No evidence of maternal cell colonization in reverted liver nodules of tyrosinemia type I patients.

BACKGROUND AND AIMS: Hereditary tyrosinemia type I (HTI) is a recessively inherited disease caused by a deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme of the tyrosine catabolic pathway. The mosaic pattern of FAH expression observed in the livers of >85% of studied patients was shown to result from the correction of the mutation in one of the FAH alleles. Bilateral cell trafficking can occur between mother and fetus and such an event could be responsible for the chimerism observed in some diseases. It also has been reported that the liver repopulation observed in a HTI murine model by serial transplantation of bone marrow-derived cells was caused by a fusion of these cells to host hepatocytes. These observations led us to test the possibility that the transfer of nucleated heterozygous maternal cells in the fetal circulation could be responsible for the mosaic liver expression of FAH in HTI patients. METHODS: We used polymorphic markers of short cytosine-adenine DNA repeats to compare DNA from corrected liver sections of 4 HTI patients with DNA from their parents' blood. RESULTS: Genotyping showed that only one maternal allele is present in DNA isolated from FAH-expressing liver nodules of each proband for at least 1 marker. CONCLUSIONS: The corrected liver nodules in HTI patients are not of maternal origin and do not support cell trafficking and cell fusion as mechanisms of correction of the gene defect in hepatocytes of tyrosinemia patients.

Female↗

PubMed2004

Intracellular sequestration of hetero-oligomers formed by wild-type and glaucoma-causing myocilin mutants.

PURPOSE: To investigate mechanism(s) by which mutations in the olfactomedin domain of myocilin (MYOC), also known as the trabecular meshwork-induced glucocorticoid response (TIGR) gene, cause autosomal dominant open-angle glaucoma, the structure and properties of wild-type (WT) MYOC protein were examined, when expressed alone or simultaneously with the Q368X or K423E disease-associated polypeptides. METHODS: Myocilin was analyzed in human aqueous humor and human trabecular meshwork (HTM) tissues. COS-7 and immortalized human trabecular meshwork (iHTM) cell lines were transfected with expression vectors encoding WT MYOC, mutated, and/or epitope-tagged cDNAs. MYOC proteins were characterized by double-epitope tagging procedures and/or Western blot analysis. RESULTS: MYOC polypeptides formed highly similar oligomers in aqueous humor, HTM tissues, transfected COS-7, and iHTM cell lines. These complexes ranged in size from 116 kDa to more than 200 kDa. The smallest complex, approximately 116 kDa, resulted from dimerization between two MYOC monomers. Expression of a 150-kDa complex was strongest in aqueous humor. Cotransfections of the WT construct with either the Q368X or K423E cDNA produced MYOC(WT)/MYOC(mutant) heterodimers and higher molecular weight hetero-oligomeric complexes. WT homo-oligomeric complexes were secreted in the extracellular media of both cell lines whereas the Q368X and K423E mutant/mutant homomultimers and heteromeric WT/mutant oligomers remained sequestered intracellularly. CONCLUSIONS: Formation of heteromeric WT/mutant complexes may provide a critical mechanism by which mutant myocilin polypeptides produce autosomal dominant open-angle glaucoma. The intracellular sequestration of abnormal WT/mutant complexes could lead to the malfunction of MYOC-expressing cells and to POAG potentially involving a dominant negative effect.

Animals↗

PubMed2002

Founder TIGR/myocilin mutations for glaucoma in the Québec population.

Primary open-angle glaucoma (POAG) is a complex disorder characterized by a progressive and treatable degeneration of the optic nerve. TIGR/myocilin (MYOC) gene mutations are found in approximately 4% of all POAG patients. Populations with frequent founder effects, such as the French-Canadians, offer unique advantages to implement genetic testing for the disorder. To assess molecular diagnosis for POAG in this population, we determined the prevalence of TIGR/MYOC mutations in 384 unrelated glaucoma patients, 38 ocular hypertensive subjects and 18 affected families (180 patients). We further analyzed the clinical features associated with these variations. Nine coding sequence variants were defined as mutations causing mostly, but not exclusively, POAG. Four families segregated distinct mutations (Gly367Arg, Gln368Stop, Lys423Glu and Pro481Leu), while 14 unrelated glaucoma patients harbored six known mutations (Thr293Lys, Glu352Lys, Gly367Arg, Gln368Stop, Lys423Glu and Ala445Val) and two novel (Ala427Thr and Arg126Trp). The frequencies of these mutations were respectively 3.8% and 22.2% in the unrelated and family studies. The Gly367Arg and Lys423Glu variants caused the earliest ages at onset. When achievable, assessment of relatives of unrelated mutation carriers showed the Arg126Trp and Gly367Arg to be familial. Characteristic allele signatures, indicative of specific founder effects, were observed for five of the six mutations conveyed by at least two patients. Recombination probability estimates suggested that the French-Canadian population had most probably inherited these six mutations from 7-10 Québec settlers. Our data demonstrated that genetic screening for TIGR/MYOC mutations should be offered to glaucoma families and to close relatives of unrelated patients aware of a family history for the disorder.

Adolescent↗

PubMed2002

Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone.

Paget disease of bone (PDB) is a common disorder characterized by focal and disorganized increases of bone turnover. Genetic factors are important in the pathogenesis of PDB. We and others recently mapped the third locus associated with the disorder, PDB3, at 5q35-qter. In the present study, by use of 24 French Canadian families and 112 unrelated subjects with PDB, the PDB3 locus was confined to approximately 300 kb. Within this interval, two disease-related haplotype signatures were observed in 11 families and 18 unrelated patients. This region encoded the ubiquitin-binding protein sequestosome 1 (SQSTM1/p62), which is a candidate gene for PDB because of its association with the NF-kappaB pathway. Screening SQSTM1/p62 for mutations led to the identification of a recurrent nonconservative change (P392L) flanking the ubiquitin-associated domain (UBA) (position 394-440) of the protein that was not present in 291 control individuals. Our data demonstrate that two independent mutational events at the same position in SQSTM1/p62 caused PDB in a high proportion of French Canadian patients.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Support for the presence of bipolar disorder susceptibility loci on chromosome 5: heterogeneity in a homogeneous population in Quebec.

A very large pedigree derived from the Saguenay-Lac-St-Jean region of Quebec contains a branch where a distal chromosome 5q haplotype seems to cosegregate with bipolar affective disorder. The authors used a diagnosis model where Bipolar Types I and II and schizoaffective disorder bipolar type were considered as affected, while single or recurrent episode major depression was classified as unknown and all the others diagnoses as unaffected. Model-free two-point LOD score values of 3.41 and 2.21 were observed at D5S432 in the 5p region with sib_ibd and sib_phase from the ASPEX package, but simulation studies did not permit the conclusion of a significant linkage because associated empirical P values were equal to .0026 and .0037. A parametric LOD score value of 2.15 was obtained at locus D5S412 in the distal chromosome 5q area. In order to investigate heterogeneity in the single multigenerational family, the pedigree was divided into five branches. Our simulation study suggested that the five branches of the Saguenay-Lac-St-Jean bipolar pedigree had low power to detect linkage under intrapedigree heterogeneity in this region.

Bipolar Disorder↗