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Biomedical subjects

G Novelli

Publications and source records attributed to G Novelli.

At least 73 records · Page 4Linked to original sources
PubMed1999

UFD1L and CDC45L: a role in DiGeorge syndrome and related phenotypes?

Molecular genetics is contributing to the understanding of normal and abnormal cardiovascular development and morphogenesis. Deletions of chromosome 22q11.2 have been associated with distinct phenotypes that result from a failure to form derivatives of third and fourth branchial arches, including DiGeorge syndrome (DGS) and velo-cardio-facial syndrome (VCFS). The biochemical mechanisms underlying these phenotypes remain undetermined. A recent study provides new insight into the mechanism by which gene deletions produce the DGS and VCFS phenotypes.

Adaptor Proteins, Vesicular Transport↗
PubMed1999

Reduction of the DM-associated homeo domain protein (DMAHP) mRNA in different brain areas of myotonic dystrophy patients.

Myotonic dystrophy (DM) is a multisystemic disease caused by expansion of a CTG trinucleotide repeat in the 3' untranslated region of the DMPK protein kinase gene on chromosome 19q13.3. The mechanism by which this expansion causes disease remains unknown. It has been suggested that CTG expansion not only affects the expression of the DMPK gene, but also alters the nuclear RNA metabolism and expression of neighboring genes. DMAHP, which is expressed in various human tissues, including skeletal muscle, heart and brain, is immediately distal to the 3' end of DMPK gene, in a CpG island which contains the CTG repeat. Here we report a 4- to 5-fold reduction of the expression of the DMAHP gene in different brain areas of DM patients. Our results demonstrate that [CTG]n expansion alters the brain DMAHP mRNA expression supporting a dominant-negative effect at the cellular level of DM [CTG]n mutation. The reduced brain expression of DMAHP could explain cerebral impairment in DM patients.

Brain Chemistry↗
PubMed1999

Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge/velo-cardio-facial syndrome.

Deletions of chromosome 22q11.2 have been associated with distinct phenotypes including DiGeorge syndrome (DGS) and velo-cardio-facial (VCFS) syndrome. These diseases result from a failure to form derivatives of the third and fourth branchial arches during development. DGS/VCFS deletions usually encompass about 3 Mb of genomic DNA in more than 90% of patients. However, deletion mapping studies have failed to demonstrate the existence of a single small region of overlap (SRO) and ruled out any obvious correlation between site or size of deletion and severity of clinical phenotype. We describe three patients carrying 'atypical' deletions presenting the DGS/VCFS phenotype. A comparative analysis of deletions in our patients and those previously published has suggested the existence of five distinct critical regions within the 22q11.2 locus. This observation argues that DGS/VCFS results from haploinsufficiency secondary to a complex and as yet unexplained molecular mechanism, probably involving chromatin effects in mediating gene expression throughout the entire region.

Child, Preschool↗
PubMed1999

Searching for psoriasis susceptibility genes in Italy: genome scan and evidence for a new locus on chromosome 1.

Psoriasis is a chronic inflammatory dermatitis, affecting approximately 2% of the population. Major clinical features include red, scaly patches on scalp, elbows, and knees, with or without severe arthritis. Several putative susceptibility loci have been mapped by parametric and non-parametric linkage analysis to chromosome regions 2p, 4q, 6p, 8q, 16q, 17q, and 20p; however, the most significant results and confirmation of linkage are only available for the 17q and 6p chromosome regions at present. In this study, 22 multiplex Italian families were investigated for linkage to 6p and 17q susceptibility regions, using a set of four microsatellites. These analyses failed to detect significant linkage with any of the examined markers. A genome-wide scan was then performed on one of the largest pedigrees, searching for an additional susceptibility locus. This study disclosed a putative linkage to chromosome 1cen-q21 markers. When these microsatellites were analyzed in the remaining families of the sample, a significant linkage was observed using both parametric and non-parametric methods. The highest two-point lod score value was obtained with D1S305 marker (3.75 at 0 = 0.05). Non-parametric analysis at this locus also demonstrated a significant excess of allele sharing (p = 0.0001).

Chromosome Mapping↗
PubMed1999

Cellular uptake and delivery monitoring of liposome/DNA complexes during in vitro transfection of CFTR gene.

The cellular uptake and distribution of cationic liposomes Dc-Chol/DOPECFTR gene complexes were assessed by electronic and confocal laser scanner microscopy (CLSM) for the CFTR gene transfer to human adenocarcinoma and tracheal epithelial cell lines. Cationic lipid forms unilamellar and multilamellar vesicles capable of rapid and efficient transport of gene into target cells. The number of fluorescent complexes was increasing with time in cells up to 6 hours showing a punctate and homogeneous DNA distribution in the cytoplasmatic and nuclear compartments, including the nucleolus. No significant difference in the biochemical and cellular behavior was observed between the investigated system and other systems previously tested. This study adds new insights into the CFTR cationic liposome-mediated gene delivery.

Cell Line↗
PubMed1999

Localization of a gene for familial patella aplasia-hypoplasia (PTLAH) to chromosome 17q21-22.

Patella aplasia-hypoplasia (PTLAH) is a rare genetic defect characterized by congenital absence or marked reduction of the patella. PTLAH can occur either as an isolated defect or in association with other malformations, and it characteristically occurs in the nail-patella syndrome and in some chromosome imbalances. We report the first evidence of linkage for isolated PTLAH in an extended Venezuelan family. After exclusion of the candidate chromosome regions where disorders associated with PTLAH have been mapped, a genomewide scan was performed that supported mapping of the disease locus within a region of 12 cM on chromosome 17q22. Two marker loci (D17S787 and D17S1604) typed from this region gave maximum LOD scores >3. Accordingly, multipoint analysis gave a maximum LOD score of 3.39, with a most likely location for the disease gene between D17S787 and D17S1604. Sequencing of the noggin gene, a candidate mapping between these markers, failed to reveal any mutation in affected subjects.

Adolescent↗
PubMed1999

Detection of an atypical 7q11.23 deletion in Williams syndrome patients which does not include the STX1A and FZD3 genes.

We present two patients with the full Williams syndrome (WS) phenotype carrying a smaller deletion than typically observed. The deleted region spans from the elastin gene to marker D7S1870. This observation narrows the minimal region of deletion in WS and suggests that the syntaxin 1A and frizzled genes are not responsible for the major features of this developmental disorder and provides important insight into understanding the genotype-phenotype correlation in WS.

Antigens, Surface↗
PubMed1998

Structure and expression of the human ubiquitin fusion-degradation gene (UFD1L).

We report the genomic organization, RNA and protein expression patterns of the gene encoding for the human homolog of the yeast ubiquitin fusion-degradation protein-1 (UFD1L). This enzyme is involved in a ubiquitin-dependent proteolytic pathway (UFD), firstly described in yeast. The human UFD1L gene is organized into 12 exons ranging in size from 33 to 161 bp. Sequence analysis of the 5'-flanking region of the gene revealed a high GC content, multiple CCAAT-binding motifs, CREB, CFT, and AP-2 sites. RNA transcripts were detected in all tissues and cell lines examined, including thymus, thymocytes, T- and B-cells, fibroblasts, chorionic villi, and amniocytes. In Western blot, the UFD1L antibody demonstrated the presence of multiple protein isoforms in all the tested tissues. Expression profile and promoter characteristics suggest UFD1L is a housekeeping gene with implications in the pathogenesis of DiGeorge/velo-cardio-facial syndrome, due to 22q11.2 deletions.

Adaptor Proteins, Vesicular Transport↗
PubMed1998

A novel frameshift mutation 840delA and a novel polymorphism D203A in the steroidogenic acute regulatory protein gene in a Japanese patient with congenital lipoid adrenal hyperplasia. Mutations in brief no. 117. Online.

Congenital lipoid adrenal hyperplasia (CLAH) is an autosomalrecessive disorder characterized by impaired production of all steroids including glucocorticoids, mineralocorticoids and sexsteriods. It has recently been reported that mutations in the steriodogenic acute regulatory protein (StAR) gene cause CLAH. We analyzed the StAR gene in a Japanese patient with CLAH. The patient was revealed to be a compound heterozygote bearing a nonsense mutation Q258X, changing codon 258 (CAG) encoding Gln to the stop codon TAG, and a novel framshift mutation 840delA resulting from deletion of one of the three adenosines normally present in codon 238 (AAA), thus leading to a frameshift after codon 237 (Thr) in the StAR gene. The patient was also revealed to be homozygous for a novel missense point mutation D203A, changing codon 203 (GAC) encoding Asp to GCC encoding Ala in the StAR gene. To elucidate the significance of the D203A mutation, we analyzed the StAR gene sequence in twenty normal subjects, and found that all of them were homozygous for the D203A mutation, indicating that the D203A mutation is an innocent polymorphism. In conclusion, we have identified a novel frameshift mutation 840delA which seems to cause 840delA and the first polymorphism D203A in the human StAR gene.

Adrenal Hyperplasia, Congenital↗
PubMed1998

Genomic instability associated with myotonic dystrophy does not involve p53 expression and activity.

We tested the hypothesis that the instability of the trinucleotide CTG at the myotonic dystrophy (DM) locus could be an intrinsic DNA damage recognisable by the p53 cell-cycle checkpoint system. p53 mRNA and protein levels were assayed in muscle biopsies and fibroblast cell lines of DM patients and unaffected controls. No differences in mRNA and protein levels were found between patients and controls, regardless of their expansion size. However, in the cells treated with adryamicin, p53 protein levels were comparable in DM and control cells. We conclude that the CTG trinucleotide expansion within the myotonin gene does not activate the p53 surveillance system, at least in adult tissues. The escape of trinucleotide expansion from the p53-mediated DNA repair system could explain some of the biological characteristics of genome instability.

Adult↗
PubMed1998

Human UDP-galactose 4' epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia.

The galactosemias are a series of three inborn errors of metabolism caused by deficiency of any one of the three human galactose-metabolic enzymes: galactokinase (GALK), galactose-1-phosphate uridyl transferase (GALT), and UDP-galactose 4' epimerase (GALE). We report here the characterization of the entire coding sequence of the GALE gene and screening for mutations in epimerase-deficient individuals. The human GALE gene is about 4 kb in size and is divided into 11 exons on chromosome band 1p36. We have identified five mutations in the GALE gene of epimerase-deficient galactosemia patients. The patients were either homozygotes or compound heterozygotes for mutations. These results confirm that epimerase-deficiency galactosemia is the result of missense mutations in the GALE gene and indicate that the disease is characterized by extensive allelic heterogeneity.

Base Sequence↗
PubMed1998

Positive correlation of CTG expansion and pharyngoesophageal alterations in myotonic dystrophy patients.

Alteration of the pharyngoesophageal musculature is a common finding in patients with myotonic dystrophy (MD), regardless of the presence of dysphagia. The aim of the present study was to determine whether a specific pattern of swallowing abnormalities could be identified in MD patients, and the possible correlation with the size of CTG repeats. Fifteen MD patients, 8 of whom were asymptomatic for dysphagia, underwent a videofluoroscopic study of swallowing. Alterations of the pharyngoesophageal phase of swallowing were detected in 12 of 15 patients, 6 without clinical evidence of dysphagia. Incomplete relaxation of the upper esophageal sphincter (UES) and esophageal hypotonia were the most common alterations. We found a significant correlation between the number of radiological alterations and the size of CTG repeats. A typical radiological pattern of swallowing has also been identified. The role of videofluoroscopy in evaluation of MD patients is briefly discussed.

Adult↗
PubMed1998

A single polymerase chain reaction-based protocol for detecting normal and expanded alleles in myotonic dystrophy.

The myotonic dystrophy (DM) expansion varies from 50 to 4000 CTG repeats in the 3' untranslated region of the DMPK gene. Direct analysis by Southern blot, after restriction enzyme digestion of genomic DNA, is the method of choice for studying the DM mutation. A long polymerase chain reaction (PCR)-formatted protocol, which involved a single genomic in vitro amplification followed by high concentration agarose gel electrophoresis and oligo-specific hybridization, was used to amplify normal alleles and DM alleles in all examined ranges of expansion (up to 3,700 CTGs) starting from a small amount of genomic DNA (> or = 15 pg). This method is quick, sensitive, and reproducible and reduces the cost of diagnostic laboratory processing.

Alleles↗