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Featured researches published by Patrizia De Bonis.


Investigative Ophthalmology & Visual Science | 2009

Linkage analysis in keratoconus: replication of locus 5q21.2 and identification of other suggestive loci.

Luigi Bisceglia; Patrizia De Bonis; Costantina Pizzicoli; Lucia Fischetti; Antonio Laborante; Michele Di Perna; Francesco Giuliani; Nicola Delle Noci; Luca Buzzonetti; Leopoldo Zelante

PURPOSE Keratoconus (KC) is the most common indication for corneal transplantation in the Western world, with etiologic mechanisms still poorly understood. The disease prevalence in the general population is approximately 1:2000, and familial aggregation, together with increased familial risk, suggests important genetic influences on its pathogenesis. To date, several loci for familial keratoconus have been described, without the identification of any responsible gene in the respective mapped intervals. The aim of this study was to identify causative/susceptibility genes for keratoconus. METHODS A total of 133 individuals (77 affected and 59 unaffected) of 25 families from southern Italy were genotyped using microsatellite markers and included in a genome-wide scan. Nonparametric and parametric analysis using an affected-only strategy were calculated by using genetic algorithm software. RESULTS The chromosomal regions 5q32-q33, 5q21.2, 14q11.2, 15q2.32 exhibited the strongest evidence of linkage by nonparametric analysis (NPL = 3.22, 2.73, 2.62, and 2.32, respectively). The regions 5q32-q33 and 14q11.2 were also supported by multipoint parametric analysis, for which heterogeneity LOD (HLOD) scores of 2.45 (alpha = 0.54) and 2.09 (alpha = 0.46), respectively, were obtained under an affected-only dominant model. CONCLUSIONS This study represents the first KC linkage replication study on the chromosomal region 5q21.2 and reports evidence of suggestive linkage in several regions for which suggestive or significant linkage has been previously detected in different populations.


Epigenetics | 2011

Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer

Lucia Anna Muscarella; Paola Parrella; Vito D’Alessandro; Annamaria la Torre; Raffaela Barbano; Andrea Fontana; Antonio Tancredi; Vito Guarnieri; Teresa Balsamo; Michelina Coco; Massimiliano Copetti; Fabio Pellegrini; Patrizia De Bonis; Michele Bisceglia; Gerardo Scaramuzzi; Evaristo Maiello; Vanna Maria Valori; Giuseppe Merla; Gianluigi Vendemiale; Vito Michele Fazio

The KEAP1/Nrf2 pathway is a master regulator of several redox-sensitive genes implicated in resistance of tumor cells against chemotherapeutic drugs. Recent data suggest that epigenetic mechanisms may play a pivotal role in the regulation of KEAP1 expression. We performed a comprehensive genetic and epigenetic analysis of the KEAP1 gene in 47 non-small cell lung cancer tissues and normal specimens. Promoter methylation analysis was performed using a quantitative methylation specific PCR assay in real time. Methylation at the KEAP1 promoter region was detected in 22 out of the 47 NSCLCs (47%) and in none of the normal tissues analyzed. Somatic mutations were detected in 7 out of the 47 tumors (15%) and loss of heterozygosity (LOH) in 10 out of the 47 (21%) of the cases. Overall, we found at least one molecular alteration in 57% of the cases. Approximately one third of the tumors had two alterations and this feature was associated with higher risk of disease progression in univariate COX regression analysis (HR = 3.62; 95% CI 1.24–10.65, p = 0.02). This result was confirmed by Kaplan-Meier analysis, which demonstrated an association between worst outcome and KEAP1 double alterations (p = 0.01, Log rank test). Our results further suggest that deregulation of the NRF2/KEAP1 system could play a pivotal role in the cancerogenesis of NSCLC. In addition identifying patients with KEAP1 genetic and epigenetic abnormalities may contribute to disease progression prediction and response to therapy in lung cancer patients.


Pediatric Nephrology | 2006

WT1 mutations in nephrotic syndrome revisited. High prevalence in young girls, associations and renal phenotypes

Filippo Aucella; Luigi Bisceglia; Patrizia De Bonis; Maddalena Gigante; Gianluca Caridi; Giancarlo Barbano; Gerolamo Mattioli; Francesco Perfumo; Loreto Gesualdo; Gian Marco Ghiggeri

WT1 mutations have been considered a rare cause of nephrotic syndrome but recent reports challenge this assumption. Exclusion of inherited forms is a basic point in any therapeutic strategy to nephrotic syndrome since they do not respond to drugs. We screened for WT1 mutations in 200 patients with nephrotic syndrome: 114 with steroid resistance (SRNS) and 86 with steroid dependence (SDNS) for whom other inherited forms of nephrotic syndrome (NPHS2, CD2AP) had been previously excluded. Three girls out of 32 of the group with steroid resistance under 18 years presented classical WT1 splice mutations (IVS9+5G>A, IVS9+4C>T) of Frasier syndrome. Another one presented a mutation coding for an amino acid change (D396N) at exon 9 that is typical of Denys-Drash syndrome. All presented resistance to drugs and developed end stage renal failure within 15 years. Two girls of the Frasier group presented a 46 XY karyotype with streak gonads while one was XX and had normal gonad morphology. In the two cases with IVS9+5G>A renal pathology was characterized by capillary wall thickening with deposition of IgG and C3 in one that was interpreted as a membrane pathology. Foam cells were diffuse in tubule-interstitial areas. In conclusion, WT1 splice mutations are not rare in females under 18 years with SRNS. This occurs in absence of a clear renal pathology picture and frequently in absence of phenotype change typical of Frasier syndrome. In adults and children with SDNS, screening analysis is of no clinical value. WT1 hot spot mutation analysis should be routinely done in children with SRNS; if the molecular screening anticipates any further therapeutic approach it may modify the long term therapeutic strategy.


Nephron Clinical Practice | 2004

Molecular analysis of NPHS2 and ACTN4 genes in a series of 33 Italian patients affected by adult-onset nonfamilial focal segmental glomerulosclerosis.

Filippo Aucella; Patrizia De Bonis; Giuseppe Gatta; Lucia Anna Muscarella; Mimmo Vigilante; Giuseppe Di Giorgio; M. D’Errico; Leopoldo Zelante; Carmine Stallone; Luigi Bisceglia

Background: Mutations in the NPHS2 gene, encoding podocin, and in the ACTN4 gene, encoding α-actinin-4, have been identified in familial childhood-onset forms of focal and segmental glomerulosclerosis (FSGS). NPHS2 may be also responsible for some sporadic cases. The role of NPHS2 and ACTN4 in the adult sporadic form of the disease is being clarifying. Methods: Thirty-three adult subjects affected by sporadic FSGS were studied at molecular level. At biopsy, 12 patients had nephrotic syndrome, 5 patients had isolated proteinuria and 16 patients showed proteinuria and hematuria. Glomerular filtration rate (GFR) was in the normal range in 19 subjects and 14 patients had a variable degree of renal failure. Multiplex families presenting with a clear familial inheritance for proteinuria or other congenital nephrotic syndrome were excluded. The whole coding region, all intron/exon boundaries and flanking intronic regions of NPHS2 gene and the exon 8, i.e. hot-spot mutations of the ACTN4 gene, were analyzed in all patients by denaturing high-performance liquid chromatography (DHPLC) to search disease-causing defects. Results: The analysis identified four already described and two new polymorphisms, IVS3–21C>T and IVS3–46C>T, on the NPHS2 gene. Moreover, the R229Q allele was identified in 3/33 patients and in 7/124 controls, accounting for an allelic frequency of 0.045 and 0.028, respectively. The new intronic polymorphism IVS7–54C>T was also found in the exon 8 of the ACTN4 gene. Conclusions: In this study, we exhaustively analyzed the NPHS2 and the exon 8 of the ACTN4 genes in a series of sporadic ‘adult-onset’ FSGS patients. No causative mutations were found while the R229Q allele was identified in 3 patients confirming its possible role as a ‘disease-associated NPHS2 allele’ although its pathogenetic involvement needs to be further clarified. Moreover, the description of new intronic polymorphisms in both genes is reported.


Molecular Genetics and Metabolism | 2010

Large rearrangements detected by MLPA, point mutations, and survey of the frequency of mutations within the SLC3A1 and SLC7A9 genes in a cohort of 172 cystinuric Italian patients

Luigi Bisceglia; Lucia Fischetti; Patrizia De Bonis; Orazio Palumbo; Bartolomeo Augello; Pietro Stanziale; Massimo Carella; Leopoldo Zelante

Cystinuria is a rare inherited disorder characterized by defective renal reabsorption of cystine and the dibasic amino acids. SLC3A1 and SLC7A9 have been identified as responsible genes. The large majority of the more than 200 mutations so far identified in the two genes are point mutations, while only few alleles carrying gross genomic alterations have been reported. We screened 39 cystinuric patients for large rearrangements, by two home-made multiplex ligation-dependent probe amplification (MLPA) assays. MLPA analysis led to the identification of 6 different alleles in SLC3A1 and 2 in SLC7A9 accounting for a total of 25 copy number changes, 11 in SLC3A1 and 14 in SLC7A9. Three large rearrangements in SLC3A1, deletion of exons 2-4 (E2_E4del), deletion of exons 5-6 (E5_E6del) and duplication of exons 8-9 (E8_E9dup) are novel. A complete SLC7A9 gene deletion was found in three patients. In addition, we report the identification of three novel point mutations in SLC7A9 (p.G105E, p.R250K, c.1416_1417insAC), the frequency and the occurrence of cystinuria mutations in a cohort of 172 Italian patients. In conclusion, we developed a reliable and robust MLPA analytic method for SLC3A1 and SLC7A9 genes that represents an optimal complement to DNA sequence analysis in patients with cystinuria, enabling the screening for deletions and duplications.


European Journal of Human Genetics | 2010

A new locus on 3p23-p25 for an autosomal-dominant limb-girdle muscular dystrophy, LGMD1H.

Luigi Bisceglia; Stefano Zoccolella; Alessandra Torraco; Maria Rosaria Piemontese; Rosa Dell'Aglio; Angela Amati; Patrizia De Bonis; Lucia Artuso; Massimiliano Copetti; Filippo M. Santorelli; Luigi Serlenga; Leopoldo Zelante; Enrico Bertini; Vittoria Petruzzella

Limb-girdle muscular dystrophies (LGMDs) are a genetically heterogeneous group of neuromuscular disorders with a selective or predominant involvement of shoulder and pelvic girdles. We clinically examined 19 members in a four-generation Italian family with autosomal-dominant LGMD. A total of 11 subjects were affected. Clinical findings showed variable expressivity in terms of age at onset and disease severity. Five subjects presented with a slowly progressive proximal muscle weakness, in both upper and lower limbs, with onset during the fourth–fifth decade of life, which fulfilled the consensus diagnostic criteria for LGMD. Earlier onset of the disease was observed in a group of patients presenting with muscle weakness and/or calf hypertrophy, and/or occasionally high CK and lactate serum levels. Two muscle biopsies showed morphological findings compatible with MD associated with subsarcolemmal accumulation of mitochondria and the presence of multiple mitochondrial DNA deletions. A genome-wide scan performed using microsatellite markers mapped the disease on chromosome 3p23–p25.1 locus in a 25-cM region between markers D3S1263 and D3S3685. The highest two-point LOD score was 3.26 (θ=0) at marker D3S1286 and D3S3613, whereas non-parametric analysis reached a P-value=0.0004. Four candidate genes within the refined region were analysed but did not reveal any mutations. Our findings further expand the clinical and genetic heterogeneity of LGMDs.


BMC Medical Genetics | 2018

Leber’s hereditary optic neuropathy, intellectual disability and epilepsy presenting with variable penetrance associated to the m.3460G >A mutation and a heteroplasmic expansion of the microsatellite in MTRNR1 gene – case report

Angelica Bianco; Luigi Bisceglia; Maria Fara De Caro; Valeria Galeandro; Patrizia De Bonis; Apollonia Tullo; Stefano Zoccolella; Silvana Guerriero; Vittoria Petruzzella

BackgroundLeber’s hereditary optic neuropathy (LHON) associated with mutations in mitochondrial DNA (mtDNA) typically manifests only optic nerve involvement but in some patients may develop additional neurological complications. The cause of this association is not clear.Case presentationWe present a case of a 24-year-old male with a history of subacute, painless, and rapidly progressive bilateral vision loss. We performed ophthalmological, neurological and neuropsychological investigations in the proband and his LHON family. The proband showed optic neuropathy, epilepsy, migraine, and intellectual disability; all the maternal relatives did not manifest optic neuropathy but a moderate to severe intellectual disability. Genetic screening revealed a novel association of the LHON m.3460G > A primary mutation with the m.T961delT + C(n)ins within the mitochondrial encoded 12S RNA (MTRNR1) gene which segregates with the intellectual disability through the maternal branch of the family. We also found a significant increase of mtDNA content in all the unaffected homo/heteroplasmic mutation carriers with respect to either affected or control subjects.ConclusionThis is the first case reporting the co-segregation of a mutation in MTRNR1 gene with a LHON primary mutation, which may be a risk factor of the extraocular signs complicating LHON phenotype. In addition, the data herein reported, confirmed that the key factor modulating the penetrance of optic atrophy in the family is the amount of mtDNA.


Journal of Human Genetics | 2016

Expanding the mutation spectrum in 130 probands with ARPKD: identification of 62 novel PKHD1 mutations by sanger sequencing and MLPA analysis

Salvatore Melchionda; Teresa Palladino; Stefano Castellana; Mario Giordano; Elisa Benetti; Patrizia De Bonis; Leopoldo Zelante; Luigi Bisceglia

Autosomal recessive polycystic kidney disease (ARPKD) is a rare severe genetic disorder arising in the perinatal period, although a late-onset presentation of the disease has been described. Pulmonary hypoplasia is the major cause of morbidity and mortality in the newborn period. ARPKD is caused by mutations in the PKHD1 (polycystic kidney and hepatic disease 1) gene that is among the largest human genes. To achieve a molecular diagnosis of the disease, a large series of Italian affected subjects were recruited. Exhaustive mutation analysis of PKHD1 gene was carried out by Sanger sequencing and multiple ligation probe amplification (MLPA) technique in 110 individuals. A total of 173 mutations resulting in a detection rate of 78.6% were identified. Additional 20 unrelated patients, in whom it was not possible to analyze the whole coding sequence, have been included in this study. Taking into account the total number (n=130) of this cohort of patients, 107 different types of mutations have been detected in 193 mutated alleles. Out of 107 mutations, 62 were novel: 11 nonsense, 6 frameshift, 7 splice site mutations, 2 in-frame deletions and 2 multiexon deletion detected by MLPA. Thirty-four were missense variants. In conclusion, our report expands the spectrum of PKHD1 mutations and confirms the heterogeneity of this disorder. The population under study represents the largest Italian ARPKD cohort reported to date. The estimated costs and the time invested for molecular screening of genes with large size and allelic heterogeneity such as PKHD1 demand the use of next-generation sequencing (NGS) technologies for a faster and cheaper screening of the affected subjects.


Pediatrics International | 2015

Familial cleidocranial dysplasia misdiagnosed as rickets over three generations

Roberto Franceschi; Evelina Maines; Michela Fedrizzi; Maria Rosaria Piemontese; Patrizia De Bonis; Nivedita Agarwal; Maria Bellizzi; Annunziata Di Palma

Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia characterized by hypoplastic clavicles, late closure of the fontanels, dental problems and other skeletal features. CCD is caused by mutations, deletions or duplications in runt‐related transcription factor 2 (RUNX2), which encodes for a protein essential for osteoblast differentiation and chondrocyte maturation. We describe three familial cases of CCD, misdiagnosed as rickets over three generations. No mutations were detected on standard DNA sequencing of RUNX2, but a novel deletion was identified on quantitative polymerase chain reaction (qPCR) and multiple ligation‐dependent probe amplification (MLPA). The present cases indicate that CCD could be misdiagnosed as rickets, leading to inappropriate treatment, and confirm that mutations in RUNX2 are not able to be identified on standard DNA sequencing in all CCD patients, but can be identified on qPCR and MLPA.


Investigative Ophthalmology & Visual Science | 2005

VSX1 mutational analysis in a series of italian patients affected by keratoconus: Detection of a novel mutation

Luigi Bisceglia; Marilena Ciaschetti; Patrizia De Bonis; Pablo Alberto Perafan Campo; Costantina Pizzicoli; Costanza Scala; Michele Grifa; Pio Ciavarella; Nicola Delle Noci; Filippo Vaira; Claudio Macaluso; Leopoldo Zelante

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Luigi Bisceglia

Casa Sollievo della Sofferenza

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Leopoldo Zelante

Casa Sollievo della Sofferenza

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Antonio Laborante

Casa Sollievo della Sofferenza

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Filippo Aucella

Casa Sollievo della Sofferenza

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Lucia Anna Muscarella

Casa Sollievo della Sofferenza

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Lucia Fischetti

Casa Sollievo della Sofferenza

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Massimiliano Copetti

Casa Sollievo della Sofferenza

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