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L Zelante

Publications and source records attributed to L Zelante.

At least 55 records · Page 3Linked to original sources
PubMed2001

The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.

In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.

Abnormalities, Multiple↗
PubMed2001

Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder.

Autistic disorder (MIM 209850) is currently viewed as a neurodevelopmental disease. Reelin plays a pivotal role in the development of laminar structures including the cerebral cortex, hippocampus, cerebellum and of several brainstem nuclei. Neuroanatomical evidence is consistent with Reelin involvement in autistic disorder. In this study, we describe several polymorphisms identified using RNA-SSCP and DNA sequencing. Association and linkage were assessed comparing 95 Italian patients to 186 ethnically-matched controls, and using the transmission/disequilibrium test and haplotype-based haplotype relative risk in 172 complete trios from 165 families collected in Italy and in the USA. Both case-control and family-based analyses yield a significant association between autistic disorder and a polymorphic GGC repeat located immediately 5' of the reelin gene (RELN) ATG initiator codon, as well as with specific haplotypes formed by this polymorphism with two single-base substitutions located in a splice junction in exon 6 and within exon 50. Triplet repeats located in 5' untranslated regions (5'UTRs) are indicative of strong transcriptional regulation. Our findings suggest that longer triplet repeats in the 5'UTR of the RELN gene confer vulnerability to autistic disorder.

Adult↗
PubMed2001

Cystinuria type I: identification of eight new mutations in SLC3A1.

BACKGROUND: Cystinuria is a heritable disorder of amino acid transport characterized by the defective transport of cystine and the dibasic amino acids through the brush border epithelial cells of the renal tubule and intestine tract. Three types of cystinuria (I, II, and III) have been described based on the urinary excretion of cystine and dibasic amino acids in obligate heterozygotes. The SLC3A1 gene coding for an amino acid transporter named rBAT is responsible for type I cystinuria, whereas the SLC7A9 gene coding for a subunit (b0,+AT) of rBAT is involved in determining non-type I (types II and III) cystinuria. METHODS: The SLC3A1 gene sequence was investigated in a sample of seven type I/type I, three type I/non-type I, six type I/untyped, and four untyped unrelated cystinuric patients by RNA single-strand conformation polymorphism (RNA-SSCP). RESULTS: Eight new point mutations (S168X, 765+1G>T, 766-2A>G, R452Q, Y461X, S547W, L564F, and C673W) and seven previously reported mutations were detected. These new mutations increase the number of mutated alleles so far characterized in SLC3A1 to 62. CONCLUSIONS: We have found SLC3A1 mutations in 0.739 of the type I chromosomes studied. The relatively high proportion of uncharacterized type I chromosomes suggests either that there may be mutations not yet found in SLC3A1 or that many of the assigned type I chromosomes in mixed type I/non-type I patients may have mutations in SLC7A9. If the hypothesis is excluded in the future, we believe that a third gene may be involved in cystinuria.

Adolescent↗
PubMed2000

Myocilin Gln368stop mutation and advanced age as risk factors for late-onset primary open-angle glaucoma.

BACKGROUND: Juvenile open-angle glaucoma has been found to be associated with molecular defects in the myocilin (MYOC) gene. Most of the defects are missense mutations located in the third exon. The Gln368stop mutation has recently been found in several cases of late-onset primary open-angle glaucoma (POAG). OBJECTIVE: To study the effect of glaucoma risk in a relatively homogeneous genetic population. METHODS: A clinical study was performed in all living members of a 5-generation family. DNA analysis was performed for studying association with genetic markers and identifying the mutation. RESULTS: We identified the Gln368stop molecular defect in 19 patients with POAG, 5 patients with ocular hypertension, and 22 healthy carriers. We compared affected and unaffected carriers based on age at onset and last examination, respectively. Besides the presence of 3 young patients with POAG (<40 years old), the number of glaucomatous patients in the advanced age group increased. CONCLUSIONS: The penetrance of glaucoma increases with age in Gln368stop carriers, but some remain unaffected at advanced age and others are affected at an early age. This suggests that additional risk factors are operating within this family, which may be identified by a genome-wide linkage search in this large pedigree. CLINICAL RELEVANCE: The myocilin Gln368stop mutation shows a good genotype-phenotype correlation and should be investigated in all familiar cases of chronic POAG. This may be important for early diagnosis and periodical checkups of presymptomatic individuals belonging to these families.

Age Factors↗
PubMed2000

Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene.

Mutations in the GJB2 gene have been identified in many patients with childhood deafness, 35delG being the most common mutation in Caucasoid populations. We have analyzed a total of 576 families/unrelated patients with recessive or sporadic deafness from Italy and Spain, 193 of them being referred as autosomal recessive, and the other 383 as apparently sporadic cases (singletons). Of the 1,152 unrelated GJB2 chromosomes analyzed from these patients, 37% had GJB2 mutations. Twenty-three different mutations were detected (1 in-frame deletion, 4 nonsense, 5 frameshift, and 13 missense mutations). Mutation 35delG was the most common, accounting for 82% of all GJB2 deafness alleles. The relative frequency of 35delG in Italy and Spain was different, representing 88% of the alleles in Italian patients and only 55% in the Spanish cases. Eight non-35delG mutations were detected more than once (V37I, E47X, 167delT, L90P, 312de114, 334delAA, R143W, and R184P), with relative frequencies ranging between 0.5 and 1.6% of the GJB2 deafness alleles. The information based on conservation of amino acid residues, coexistence with a second GJB2 mutation or absence of the mutation in non-deaf control subjects, suggests that most of these missense changes should be responsible for the deafness phenotype.

Alleles↗
PubMed2000

High carrier frequency of the 35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 35delG.

Congenital deafness accounts for about 1 in 1000 infants and approximately 80% of cases are inherited as an autosomal recessive trait. Recently, it has been demonstrated that connexin 26 (GJB2) gene is a major gene for congenital sensorineural deafness. A single mutation (named 35delG) was found in most recessive families and sporadic cases of congenital deafness, among Caucasoids, with relative frequencies ranging from 28% to 63%. We present here the analysis of the 35delG mutation in 3270 random controls from 17 European countries. We have detected a carrier frequency for 35delG of 1 in 35 in southern Europe and 1 in 79 in central and northern Europe. In addition, 35delG was detected in five out of 376 Jewish subjects of different origin, but was absent in other non-European populations. The study suggests either a single origin for 35delG somewhere in Europe or in the Middle East, and the possible presence of a carrier advantage together with a founder effect. The 35delG carrier frequency of 1 in 51 in the overall European population clearly indicates that this genetic alteration is a major mutation for autosomal recessive deafness in Caucasoids. This finding should facilitate diagnosis of congenital deafness and allow early treatment of the affected subjects.

Connexin 26↗
PubMed2000

Transforming growth factor-beta1 gene polymorphism, bone turnover, and bone mass in Italian postmenopausal women.

Transforming growth factor beta1 (TGF-beta1) is abundant in bone and is an important regulator of the osteoclastic-osteoblastic interaction (coupling). The sequence variation, 713-8delC in the TGF-beta1 gene has previously been found to be associated with very low bone mass in osteoporotic women and with increased bone turnover in both osteoporotic and normal women. The possible association of this polymorphism with bone mass and bone turnover has now been investigated in 256 postmenopausal Italian women. A significant association of TGF-beta1 with bone mass was detected in the populations. Subjects carrying the sequence variation 713-8delC (Tt) genotype showed a significantly lower bone mineral density (BMD) at the hip than those without sequence variation in the genotype (TT). Individuals carrying the tt genotype have a more severe osteoporosis (P=0.0001 vs. TT and Tt genotypes). The frequency of the fragility fractures was significantly lower in individuals with TT genotype than in those with the Tt and tt genotypes (X2=21.9; P=0.006). Furthermore a significant association was found between 713-8delC and bone turnover. The results suggest a strong evidence for an association among the 713-8delC allele of the TGF-beta1 gene and the femoral BMD, the prevalence of osteoporotic fractures, and finally a high bone turnover in a sample of Italian postmenopausal women.

Aged↗
PubMed2000

Hereditary thrombocytopenia due to reduced platelet production--report on two families and mutational screening of the thrombopoietin receptor gene (c-mpl).

Hereditary thrombocytopenias represent heterogeneous clinical and genetic syndromes. They include a consistent group of families which are considered as a separate clinical entity, characterized by autosomal dominant transmission, incomplete penetrance in females, chronic thrombocytopenia with early age of onset and frequently increased platelet volume, without any other hematologic abnormality. The molecular defect in these families is still unknown. We describe 2 families in 3 generations (10 patients), and report the first study of the TPO/c-mpl system in autosomal dominant thrombocytopenia. We performed mutational screening of c-mpl coding, flanking introns and promoter regions in 2 probands from the two families by DNA sequencing. The results do not provide evidence of c-mpl sequence alterations in either of the 2 families investigated. Moreover, the normal TPO serum levels detected in 5 patients from each family leads us to exclude the possibility of a defect in TPO production in our families. Finally, the involvement of both c-mpl and TPO genes in the pathogenesis of thrombocytopenia in these two families was excluded by negative results of linkage analysis.

Adolescent↗
PubMed1999

Characterization of copine VII, a new member of the copine family, and its exclusion as a candidate in sporadic breast cancers with loss of heterozygosity at 16q24.3.

In a search for candidate tumor suppressor genes within a 650-kb common region of loss of heterozygosity (LOH) at 16q24.3 in breast cancer tissues, a 2.6-kb cDNA, named copine VII (CPNE7), was characterized. The gene is 2654 bp and codes for a 633-residue protein with high homology to the other members of the copine family, such as copine I, copine III, and N-copine. The predicted amino acid sequence contains two copies of a C2 domain in the N-terminus. Since these domains have been found in several membrane-binding proteins involved in different intracellular processes, copine VII was viewed as a potential tumor suppressor gene. Mutation analysis was carried out by single-strand conformation polymorphism analysis of 18 breast tumor tissue samples with ascertained LOH on chromosome 16q24.3. Since only two polymorphisms were identified, no evidence was found to indicate that copine VII is the tumor suppressor gene at 16q24.3 involved in breast cancer.

Amino Acid Sequence↗
PubMed1999

Recombinant families locate the gene for non-type I cystinuria between markers C13 and D19S587 on chromosome 19q13.1.

Cystinuria is an autosomal recessive aminoaciduria in which three urinary phenotypes have been described. The gene responsible for type I, SLC3A1, encodes the amino acid transporter rBAT. This gene is not responsible for types II or III. Recently the type III locus (CSNU3) was mapped by two groups to overlapping 6-Mb regions on chromosome 19q. In the present study, we restrict the critical region for non-type I cystinuria to 2.4 Mb by recombination analysis in Italian, German, and Spanish families. For this purpose, we have used the microsatellite markers described in the region plus new microsatellites that we have developed. Our results locate the non-type I cystinuria gene in an interval flanked by the markers C13 and D19S587, which are about 2.8 cM apart.

Chromosome Mapping↗
PubMed1999

Acrodysplasia, severe ossification abnormalities with short stature, and fibular hypoplasia.

We present a girl with short stature, growth hormone neurosecretory dysfunction, severe hypoplastic/aplastic changes of the bones of the hands and feet with dysharmonic ossification, severely delayed bone age, microcrania, and fibular hypoplasia. Parental consanguinity suggests autosomal recessive inheritance. An additional three cases [Eiken et al., 1984: Eur J Pediatr 141: 231-235] sharing some of the radiographic manifestations of this patient have been reported. However, distinctive findings in the present case seem to outline a separate entity.

Age Determination by Skeleton↗
PubMed1999

Familial pseudohyperkalemia maps to the same locus as dehydrated hereditary stomatocytosis (hereditary xerocytosis).

Familial pseudohyperkalemia is a "leaky red blood cell" condition in which the cells show a temperature-dependent loss of potassium (K) from red blood cells when stored at room temperature, manifesting as apparent hyperkalemia. The red blood cells show a reduced lifespan in vivo but there is no frank hemolysis. Studies of cation content and transport show a marginal increase in permeability at 37 degrees C and a degree of cellular dehydration, qualitatively similar to the changes seen in dehydrated hereditary stomatocytosis (hereditary xerocytosis). Physiological studies have shown that the passive leak to K has an abnormal temperature dependence, such that the leak is less sensitive to temperature than that in normal cells. We performed genetic mapping on the original family and found that the condition in this kindred maps to the same locus (16q23-ter) that we have previously identified for an Irish family with dehydrated hereditary stomatocytosis, which does not show the same temperature effects.

Anemia, Hemolytic, Congenital↗
PubMed1999

The PISSLRE gene: structure, exon skipping, and exclusion as tumor suppressor in breast cancer.

In sporadic breast cancer, loss of heterozygosity (LOH) frequently occurs in three discrete regions of the long arm of chromosome 16q, the most telomeric of which is located at 16q24.3. Among the genes mapped to this region, PISSLRE is a plausible candidate tumor suppressor gene. It codes for a putative cyclin-dependent kinase that, as with other members of this family, is likely to be involved in regulating the cell cycle and therefore may have a role in oncogenesis. We characterized the genomic structure of PISSLRE and found that the splicing of this gene is complex. A variety of different transcripts were identified, including those due to cryptic splice sites, exon skipping, insertion of intronic sequences, and exon scrambling. The last phenomenon was observed in a rare PISSLRE transcript in which exons are joined at a nonconsensus splice site in an order different from that predicted by the genomic sequence. To screen the PISSLRE gene in breast tumors with ascertained LOH at 16q24.3, we have analyzed each exon by single-strand conformational polymorphism. No variation was found in the coding sequence, leading us to conclude that another tumor suppressor must be targeted by LOH in sporadic breast cancer.

Alternative Splicing↗
PubMed1999

Splice-site mutation in the PDS gene may result in intrafamilial variability for deafness in Pendred syndrome.

Pendred syndrome is a recessive inherited disorder that consists of developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter). This disorder may account for up to 10% of cases of hereditary deafness. The disease gene (PDS) has been mapped to chromosome 7q22-q31, and encodes a chloride-iodide transport protein. We performed mutation analysis of individual exons of the PDS gene in one Spanish family that shows intrafamilial variability of the deafness phenotype (two patients with profound and one with moderate-severe deafness). We identified a new splice-site mutation affecting intron 4 of the PDS gene, at nucleotide position 639+7. RNA analysis from lymphocytes of the affected patients showed that mutation 639+7A-->G generates a new donor splice site, leading to an mRNA with an insertion of six nucleotides from intron 4 of PDS. Since the newly created donor splice site is likely to compete with the normal one, variations of the levels of normal and aberrant transcripts of the PDS gene in the cochlea may explain the variability in the deafness presentation.

Amino Acid Sequence↗
PubMed1999

Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals.

Nevoid basal cell carcinoma syndrome (NBCCS) is a hereditary condition transmitted as an autosomal dominant trait with complete penetrance and variable expressivity. The syndrome is characterised by numerous basal cell carcinomas (BCCs), odontogenic keratocysts of the jaws, palmar and/or plantar pits, skeletal abnormalities and intracranial calcifications. In this paper, the clinical features of 37 Italian patients are reviewed. Jaw cysts and calcification of falx cerebri were the most frequently observed anomalies, followed by BCCs and palmar/plantar pits. Similar to the case of African Americans, the relatively low frequency of BCCs in the Italian population is probably due to protective skin pigmentation. A future search based on mutation screening might establish a possible genotype phenotype correlation in Italian patients.

Adolescent↗
PubMed1999

Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT.

Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.

Amino Acid Sequence↗