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Biomedical subjects

G Novelli

Publications and source records attributed to G Novelli.

At least 127 records · Page 7Linked to original sources
PubMed1995

Survival motor neuron gene transcript analysis in muscles from spinal muscular atrophy patients.

We have identified and characterized four different mRNA isoforms of the survival motor neuron (SMN) gene from skeletal muscle of 9 SMA patients and 15 unaffected controls. These isoforms appear to be generated by combinatorial splicing of both exons 5 and 7 of the SMN telomeric and centromeric gene copies. The full-size and the truncated SMN-1b isoforms of the telomeric SMN copy are significantly reduced in muscle of SMA patients, irrespective of the disease types. Our results suggest that multiple RNA splicing is operative in the two SMN-related genes and that SMN-related polypeptides may be active in the muscle.

Alternative Splicing↗
PubMed1995

Two pedigrees of autosomal dominant atrioventricular canal defect (AVCD): exclusion from the critical region on 8p.

Atrioventricular canal defects (AVCD) constitute the predominant congenital heart defect in Down syndrome. For this reason, a candidate gene involved in atrioventricular canal development was previously searched and excluded in dominant pedigrees of AVCD, using linkage analysis of polymorphisms from chromosome 21. Because of the striking association between 8p deletion and AVCD, a search for an AVCD gene was carried out in two pedigrees of individuals with autosomal dominant AVCD using a set of DNA markers of the 8pter-->q12 region. These two families include affected individuals and subjects who have transmitted the defect but are not clinically affected. Two-point lod scores were significantly negative for all markers at penetrance levels of 90% and 50%. Multipoint analysis excluded the region covered by the markers LPL-D8S262 and 30 cM to either side of this area. This result corroborates heterogeneity of this heart defect and indicates that the genetic basis of familial AVCD is different from AVCD associated to either trisomy 21 or 8p deletion.

Child↗
PubMed1995

Analysis of the elastin gene in 60 patients with clinical diagnosis of Williams syndrome.

Williams syndrome (WS) is caused by deletion of the elastin (ELN) gene. We have analyzed an intragenic restriction fragment length polymorphism (RFLP) and the gene dosage of ELN using a new probe (FP4) in a series of 60 sporadic patients with a clinical diagnosis of WS. Deletion of the ELN gene was shown in 54 cases, while clinical revaluation of the 6 patients without the deletion did not confirm the diagnosis of WS. These results support the genetic homogeneity of WS, and the high accuracy of ELN molecular analysis, which can be confidenty used for providing genetic counselling to WS families.

Adolescent↗
PubMed1995

22q11 deletions in isolated and syndromic patients with tetralogy of Fallot.

Tetralogy of Fallot (TF) is a congenital conotruncal heart defect commonly found in DiGeorge (DGS) and velo-cardio-facial (VCFS) syndromes. The deletion of chromosome 22q11 (del22q11) is a well established cause of DGS and VCFS, and it has been demonstrated also in sporadic or familial cases of TF. In order to investigate the prevalence of del22q11 in patients with TF, we analyzed the DNA of 137 consecutive patients with syndromic and isolated TF, using the HD7k probe, which detects hemizygosity for the D22S134 locus. Del22q11 has been detected in 11/26 (42%) syndromic patients. Evidence for hemizygosity was obtained in all patients with DGS and in 8/15 patients with VCFS. None of the 107 patients with isolated TF had del22q11. Our experience suggests that children with TF and del22q11 always present major or minor extracardiac anomalies. These features, including subtle facial dysmorphisms, should be checked routinely in patients with TF and other conotruncal heart defects.

Adolescent↗
PubMed1995

Postzygotic instability of the myotonic dystrophy p[AGC] in repeat supported by larger expansions in muscle and reduced amplifications in sperm.

We have analysed the [AGC] expansion in leucocytes, muscle and sperm from 17 individuals affected by myotonic dystrophy (DM). Skeletal muscle showed a larger repeat number than leucocytes in the same patient. A similar degree of expansion was detected in differently affected muscles of a single patient. The germline mutation (< or = 350 repeats) was expanded in somatic cells of the progeny in all patients examined. Our results provide evidence of an early postzygotic instability of the [AGC] repeat in DM.

Adolescent↗
PubMed1995

Correlation between cardiac involvement and CTG trinucleotide repeat length in myotonic dystrophy.

OBJECTIVES: Because sudden death due to complete atrioventricular (AV) block or ventricular arrhythmias is the most dramatic event in myotonic dystrophy, we assessed the relation of cardiac disease to cytosine-thymine-guanine (CTG) triplet mutation in adults affected with myotonic dystrophy. BACKGROUND: The myotonic dystrophy mutation, identified as an unstable deoxyribonucleic acid (DNA) sequence (CTG) prone to increase the number of trinucleotide repeats, produces clinical manifestations of the disease in skeletal muscle, the heart and many organ systems. METHODS: Forty-two adult patients underwent electrocardiography and echocardiography; in addition, signal-averaging electrocardiography was performed in 22, and 24-h Holter monitoring was recorded in 32. The diagnosis was established by neurologic examination, electromyography, muscle biopsy and DNA analysis. The patients were then classified into three subgroups on the basis of the number of CTG trinucleotide repeat expansions: E1 = 18 patients with 0 to 500 CTG repeats; E2 = 12 patients with up to 1,000 repeats; E3 + E4 = 10 patients with up to 1,500 repeats and 2 patients with > 1,500 repeats. RESULTS: The incidence of normal electrocardiographic (ECG) results was found to be significantly different in the three subgroups (55%, 50%, 17% in E1, E2, E3, + E4, respectively, p = 0.04), with the highest values in the group with fewer repeat expansions. The incidence of complete left bundle branch block was also significantly different among the groups (5% in E1, 0% in E2, 42% in E3 + E4 p = 0.01) and was directly correlated with the size of the expansion. A time-domain analysis of the signal-averaged ECG obtained in 12 patients in E1, 4 in E2, 5 in E3 and 1 in E4 showed that abnormal ventricular late potentials were directly correlated with CTG expansion (33% in E1, 75% in E2, 83% in E3 + E4, p = 0.05). Moreover, the incidence of ventricular couplets or triplets showed a positive correlation with size of CTG expansion (0 in E1, 0 in E2, 29% in E3 + E4, chi square 0.02). CONCLUSIONS: Our findings suggest that the involvement of specialized cardiac tissue, accounting for severe AV and intraventricular conduction defects, is related to CTG repeat length. In addition, the presence of abnormal late potentials directly correlates to CTG expansion. Abnormal late potentials, caused by slowed and fragmented conduction through damaged areas of myocardium, represent a substrate for malignant reentrant ventricular arrhythmias. In the future, therefore, molecular analysis of DNA should identify patients with cardiac disease at high risk for development of AV block or lethal ventricular arrhythmias.

Adolescent↗
PubMed1995

The link between cytogenetics and mendelism.

High resolution chromosome analysis, molecular cytogenetics, and study of the association between specific chromosome rearrangements and single gene disorders have provided a chromosomal basis to a number of mendelian diseases. Deletions and duplications of small regions, usually less than 3 Mb in size, result in an alteration of normal gene dosage of a number of unrelated genes physically close to each other and are responsible for contiguous gene syndromes. For example, haploinsufficiency is implicated for del 8q24.1 in Langer-Giedion syndrome, del 17p13.3 in Miller-Dieker syndrome, and del 22q11.2 in DiGeorge and Velo-cardiofacial syndromes. Another chromosomal mechanism causing mendelian phenotypes is translocation, which may eventually interrupt a disease gene. It is assumed that translocation breakpoints are running through a relevant gene, hindering the production of the gene product. An example is breakage 16p13.3 associated with Rubinstein-Taybi syndrome. Females with X/autosome translocations have an almost exclusive inactivation of the normal X. Interruption of a disease gene in the translocated X causes the expression of a mendelian phenotype in the presence of an allelic recessive mutation onto the nonrearranged X. Finally, if a human gene shows exclusive expression from a single parental homologue, ie, it is imprinted, deletion of the chromosomal segment containing the active allele results in structural monosomy and functional nullisomy. This situation is illustrated by Prader-Willi and Angelman syndromes. Over seventy human genes have been precisely assigned to chromosomal regions using a cytogenetic approach. Chromosome techniques combined with molecular methods have proved to have powerful and sensitive diagnostic capabilities.

Chromosome Deletion↗
PubMed1995

Discordant clinical outcome in myotonic dystrophy relatives showing (CTG)n > 700 repeats.

A myotonic dystrophy (DM) family is described in which discordant DM phenotypes were found in the children of two affected sisters with similar CTG expansion and clinical manifestations. In this family, congenital as well as early severe childhood and later childhood onset DM coexist. This observation strengthens the limited ability of lymphocytes CTG repeat number analysis in predicting genotype-phenotype correlations in DM patients.

Adolescent↗
PubMed1995

Identification of six novel CFTR mutations in a sample of Italian cystic fibrosis patients.

The spectrum of cystic fibrosis (CF) mutations has been determined in many populations of different ethnic and geographic origins. However, in the south of Europe, the commonest mutation, delta F508, accounts for only about 50% of CF chromosomes, while identification of most of the other mutant alleles has not been achieved. In an ongoing effort to identify these alleles, we have scanned the entire coding sequences of the CF gene using a GC clamp denaturing gradient gel electrophoresis assay in a sample of 57 chromosomes from patients of italian origin. We have identified six novel mutations (C276X, H139R, R117L, S42F, A1006E and 3121-2A---> T). Each has only been found once in this sample of CF patients.

Alleles↗
PubMed1995

Neonatal spinal muscular atrophy with diaphragmatic paralysis is unlinked to 5q11.2-q13.

Two sibs affected by the severe neonatal form of spinal muscular atrophy (SMA) with diaphragmatic paralysis are described. The two sibs were discordant for the haplotypes determined by DNA markers flanking the SMA locus. This supports non-linkage of SMA to chromosome 5 in this family and indicates that the uncommon SMA type I variant associated with early onset respiratory failure maps outside the 5q11.2-q13.3 region.

Adult↗
PubMed1995

Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients.

Congenital bilateral absence of the vas deferens (CBAVD) is an important cause of sterility in men. Although the genetic basis of this condition is still unclear, it has been shown recently that some of these patients carry mutations in their cystic fibrosis transmembrane conductance regulator (CFTR) genes. To extend this observation, we have analyzed the entire coding sequence of the CFTR gene in a cohort of 67 men with CBAVD, who are otherwise healthy. We have identified four novel missense mutations (A800G, G149R, R258G, and E193K). We have shown that 42% of subjects were carriers of one CFTR allele and that 24% are compound heterozygous for CFTR alleles. Thus, we have been unable to identify 76% of these patients as carrying two CFTR mutations. Furthermore, we have described the segregation of CFTR haplotypes in the family of one CBAVD male; in this family are two male siblings, with identical CFTR loci but displaying different phenotypes, one of them being fertile and the other sterile. The data presented in this family, indicating a discordance between the CBAVD phenotype and a marked carrier (delta F508) chromosome, support the involvement of another gene(s), in the etiology of CBAVD.

Alleles↗
PubMed1994

Prenatal diagnosis of X-linked retinitis pigmentosa (RP) in five pregnancies at risk.

Five pregnancies at risk for X-linked retinitis pigmentosa (RP) have been monitored by first-trimester prenatal diagnosis using DNA markers flanking the RP2 and RP3 loci. Three affected and two unaffected fetuses, including a female carrying a wild-type genotype, were predicted on the basis of marker segregation and estimation of the recombination fraction.

DNA Probes↗
PubMed1994

First-trimester prenatal diagnosis of spinal muscular atrophy using microsatellite markers.

Twenty-five pregnancies at risk for spinal muscular atrophy I (SMA I) have been monitored by first-trimester prenatal diagnosis. Microsatellite markers were used in all cases to amplify polymorphic regions at the D5S125, D5S435, D5S39, D5S127, and D5S112 loci. All families, including 12 SMA I pedigrees with a decreased index child, were fully informative for DNA analysis. Three fetuses were predicted to be affected and 22 fetuses were predicted to be unaffected. Twenty-two newborns were unaffected by clinical examination at birth. These results support the accuracy of SMA I prenatal diagnosis based on linkage analysis.

Base Sequence↗