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ABSTRACT: A 31 years old Caucasian male was referred for panhypopituitarism resulting from an operated craniopharyngioma. The patient had been previously submitted to kidney transplantation for end-stage-renal-disease due to X-linked Alport syndrome (ATS). Subsequent Quantitative-Fluorescent-Polymerase-Chain-Reaction-analysis indicated a 47,XXY-karyotype, consistent with Klinefelter syndrome (KS). The relevance of this unique case stems from several issues: i) KS was an unexpected finding due to a previous diagnosis of hypogonadotropic hypogonadism resulting from craniopharyngioma; ii) the discovery of a de novo p.G406S substitution causing ATS; iii) the multifactor origin of severe sexual dysfunction. This is the first description of the co-occurrence of KS, ATS and craniopharyngioma.
Journal of Andrology 04/2012; · 2.97 Impact Factor
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Rosangela Artuso,
Chiara Fallerini,
Laura Dosa,
Francesca Scionti,
Maurizio Clementi,
Guido Garosi,
Laura Massella,
Maria Carmela Epistolato,
Roberta Mancini,
Francesca Mari, Ilaria Longo,
Francesca Ariani,
Alessandra Renieri,
Mirella Bruttini
[show abstract]
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ABSTRACT: Alport syndrome (ATS) is a hereditary nephropathy often associated with sensorineural hypoacusis and ocular abnormalities. Mutations in the COL4A5 gene cause X-linked ATS. Mutations in COL4A4 and COL4A3 genes have been reported in both autosomal recessive and autosomal dominant ATS. The conventional mutation screening, performed by DHPLC and/or Sanger sequencing, is time-consuming and has relatively high costs because of the absence of hot spots and to the high number of exons per gene: 51 (COL4A5), 48 (COL4A4) and 52 (COL4A3). Several months are usually necessary to complete the diagnosis, especially in cases with less informative pedigrees. To overcome these limitations, we designed a next-generation sequencing (NGS) protocol enabling simultaneous detection of all possible variants in the three genes. We used a method coupling selective amplification to the 454 Roche DNA sequencing platform (Genome Sequencer junior). The application of this technology allowed us to identify the second mutation in two ATS patients (p.Ser1147Phe in COL4A3 and p.Arg1682Trp in COL4A4) and to reconsider the diagnosis of ATS in a third patient. This study, therefore, illustrates the successful application of NGS to mutation screening of Mendelian disorders with locus heterogeneity.
European journal of human genetics: EJHG 09/2011; 20(1):50-7. · 3.56 Impact Factor
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Paolo Frezzotti,
Chiara Pescucci,
Filomena Tiziana Papa,
Michele Iester,
Vincenzo Mittica,
Ilaria Motolese,
Sabrina Peruzzi,
Rosangela Artuso, Ilaria Longo,
Maria Antonietta Mencarelli,
Pietro Mittica,
Eduardo Motolese,
Alessandra Renieri
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ABSTRACT: To assess the involvement of WDR36 sequence variance in primary open-angle glaucoma (POAG) in Italian patients.
A cohort of 34 Italian families affected by POAG was analysed by denaturing high-performance liquid chromatography for mutation in the WDR36 gene. Among the 34 families enrolled, 25 were affected by high-tension glaucoma (HTG), four by juvenile open-angle glaucoma and one by normal tension glaucoma. In addition, four families presented both juvenile open-angle glaucoma and HTG-POAG patients within the same pedigree.
Four previously identified intronic polymorphisms (IVS5+30C→T; IVS12+90 G→T; IVS13+89G→A; IVS16-30A→G) and a novel one (IVS21-75G→A) have been identified. In addition, one proband was found to carry the p.D658G mutation reported as the more recurrent disease-causing allele.
The findings suggest that WDR36 sequence variance is only a rare cause of glaucoma in Italian families. Clearly, investigation of additional families with extensive studies is needed to clarify the role of WDR36 in the pathophysiology of glaucoma.
The British journal of ophthalmology 05/2011; 95(5):624-6. · 2.92 Impact Factor
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Veronica Parri,
Eleni Katzaki,
Vera Uliana,
Francesca Scionti,
Rossella Tita,
Rosangela Artuso, Ilaria Longo,
Renske Boschloo,
Raymon Vijzelaar,
Angelo Selicorni, [......],
Sabrina Buoni,
Joussef Hayek,
Laurent Servais,
Bert B A de Vries,
Nelly Georgoudi,
Sheena Nakou,
Michael B Petersen,
Francesca Mari,
Alessandra Renieri,
Francesca Ariani
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ABSTRACT: Cohen syndrome is a rare, clinically variable autosomal recessive disorder characterized by mental retardation, postnatal microcephaly, facial dysmorphisms, ocular abnormalities and intermittent neutropenia. Mutations in the COH1 gene have been found in patients from different ethnic origins. However, a high percentage of patients have only one or no mutated allele. To investigate whether COH1 copy number changes account for missed mutations, we used multiplex ligation-dependent probe amplification (MLPA) to test a group of 14 patients with Cohen syndrome. This analysis has allowed us to identify multi-exonic deletions in 11 alleles and duplications in 4 alleles. Considering our previous study, COH1 copy number variations represent 42% of total mutated alleles. To our knowledge, COH1 intragenic duplications have never been reported in Cohen syndrome. The three duplications encompassed exons 4-13, 20-30 and 57-60, respectively. Interestingly, four deletions showed the same exon coverage (exons 6-16) with respect to a deletion recently reported in a large Greek consanguineous family. Haplotype analysis suggested a possible founder effect in the Mediterranean basin. The use of MLPA was therefore crucial in identifying mutated alleles undetected by traditional techniques and in defining the extent of the deletions/duplications. Given the high percentage of identified copy number variations, we suggest that this technique could be used as the initial screening method for molecular diagnosis of Cohen syndrome.
European journal of human genetics: EJHG 05/2010; 18(10):1133-40. · 3.56 Impact Factor
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Katia Sampieri,
Maria Antonietta Mencarelli,
Maria Carmela Epistolato,
Paolo Toti,
Stefano Lazzi,
Mirella Bruttini,
Sonia De Francesco, Ilaria Longo,
Ilaria Meloni,
Francesca Mari,
Antonio Acquaviva,
Theodora Hadjistilianou,
Alessandra Renieri,
Francesca Ariani
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ABSTRACT: Introduction. Genomic copy number changes are involved in the multi-step process transforming normal retina in retinoblastoma after RB1 mutational events. Previous studies on retinoblastoma samples led to a multi-step model in which after two successive RB1 mutations, further genomic changes accompany malignancy: 1q32.1 gain is followed by 6p22 gain, that in turn is followed by 16q22 loss and 2p24.1 gain. Retinoma is a benign variant of retinoblastoma that was initially considered a tumor regression, but recent evidences suggest that it rather represents a pre-malignant lesion. Genetic studies on retinoma tissue have rarely been performed. Materials and methods. We investigated by Real-Time qPCR, copy number changes of candidate genes located within the 4 hot-spot regions (MDM4 at 1q32.1, MYCN at 2p24.1, E2F3 at 6p22 and CDH11 at 16q22) in retina, retinoma and retinoblastoma tissues from two different patients. Results. Our results demonstrated that some copy number changes thought to belong to early (MDM4 gain) or late stage (MYCN and E2F3 gain) of retinoblastoma are already present in retinoma at the same (for MDM4) or at lower (for MYCN and E2F3) copy number variation respect to retinoblastoma. CDH11 copy number is not altered in the two retinoma samples, but gain is present in one of the two retinoblastomas. Discussion. Our results suggest that MDM4 gain may be involved in the early transition from normal retina to retinoma, while MYCN and E2F3 progressive gain may represent driving factors of tumor progression. These results also confirm the pre-malignant nature of retinoma.
07/2009; 47(8):1483-1492.
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Elena Marcocci,
Vera Uliana,
Mirella Bruttini,
Rosangela Artuso,
Margherita Cirillo Silengo,
Marlenka Zerial,
Franco Bergesio,
Antonio Amoroso,
Silvana Savoldi,
Marco Pennesi, [......],
Giuseppe Rombolà,
Giovanni Battista Fogazzi,
Cristina Rosatelli,
Ciro Dresch Martinhago,
Mario Carmellini,
Roberta Mancini,
Giuseppina Di Costanzo, Ilaria Longo,
Alessandra Renieri,
Francesca Mari
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ABSTRACT: Alport syndrome is a clinically and genetically heterogeneous nephropathy characterized by glomerular basement membrane lesions often associated with hearing loss and ocular anomalies. While the X-linked and the autosomal recessive forms are well known, the autosomal dominant form is not well acknowledged.
We have clinically investigated 38 patients with a diagnosis of autosomal dominant Alport syndrome belonging to eight different families. The analysis of the COL4A4 gene was performed by denaturing high performance liquid chromatography and automated DNA sequencing.
In our cohort of patients, only 24.3% (9/37) reached end-stage renal disease, at the mean age of 51.2 years. Four patients had hearing loss (13.3%) and none ocular changes. Molecular analysis revealed eight novel private COL4A4 gene mutations: three frameshift, three missense and two splice-site mutations.
These data indicate autosomal dominant Alport syndrome as a disease with a low risk of ocular and hearing anomalies but with a significant risk to develop renal failure although at an older age than the X-linked form. We were unable to demonstrate a genotype-phenotype correlation. Altogether, these data make difficult the differential diagnosis with the benign familial haematuria due to heterozygous mutations of COL4A4 and COL4A3, especially in young patients, and with the X-linked form of Alport syndrome in families where only females are affected. A correct diagnosis and prognosis is based on a comprehensive clinical investigation in as many family members as possible associated with a broadly formal genetic analysis of the pedigree.
Nephrology Dialysis Transplantation 02/2009; 24(5):1464-71. · 3.40 Impact Factor
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Katia Sampieri,
Mariangela Amenduni,
Filomena Tiziana Papa,
Eleni Katzaki,
Maria Antonietta Mencarelli,
Annabella Marozza,
Maria Carmela Epistolato,
Paolo Toti,
Stefano Lazzi,
Mirella Bruttini,
Roberta De Filippis,
Sonia De Francesco, Ilaria Longo,
Ilaria Meloni,
Francesca Mari,
Antonio Acquaviva,
Theodora Hadjistilianou,
Alessandra Renieri,
Francesca Ariani
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ABSTRACT: In retinoblastoma, two RB1 mutations are necessary for tumor development. Recurrent genomic rearrangements may represent subsequent events required for retinoblastoma progression. Array-comparative genomic hybridization was carried out in 18 eye samples, 10 from bilateral and eight from unilateral retinoblastoma patients. Two unilateral cases also showed areas of retinoma. The most frequent imbalance in retinoblastomas was 6p gain (40%), followed by gains at 1q12-q25.3, 2p24.3-p24.2, 9q22.2, and 9q33.1 and losses at 11q24.3, 13q13.2-q22.3, and 16q12.1-q21. Bilateral cases showed a lower number of imbalances than unilateral cases (P = 0.002). Unilateral cases were divided into low-level (< or = 4) and high-level (> or = 7) chromosomal instability groups. The first group presented with younger age at diagnosis (mean 511 days) compared with the second group (mean 1606 days). In one retinoma case ophthalmoscopically diagnosed as a benign lesion no rearrangements were detected, whereas the adjacent retinoblastoma displayed seven aberrations. The other retinoma case identified by retrospective histopathological examination shared three rearrangements with the adjacent retinoblastoma. Two other gene-free rearrangements were retinoma specific. One rearrangement, dup5p, was retinoblastoma specific and included the SKP2 gene. Genomic profiling indicated that the first retinoma was a pretumoral lesion, whereas the other represents a subclone of cells bearing 'benign' rearrangements overwhelmed by another subclone presenting aberrations with higher 'oncogenic' potential. In summary, the present study shows that bilateral and unilateral retinoblastoma have different chromosomal instability that correlates with the age of tumor onset in unilateral cases. This is the first report of genomic profiling in retinoma tissue, shedding light on the different nature of lesions named 'retinoma'.
Cancer Science 01/2009; 100(3):465-71. · 3.33 Impact Factor
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Francesca Ariani,
Giuseppe Hayek,
Dalila Rondinella,
Rosangela Artuso,
Maria Antonietta Mencarelli,
Ariele Spanhol-Rosseto,
Marzia Pollazzon,
Sabrina Buoni,
Ottavia Spiga,
Sara Ricciardi,
Ilaria Meloni, Ilaria Longo,
Francesca Mari,
Vania Broccoli,
Michele Zappella,
Alessandra Renieri
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ABSTRACT: Rett syndrome is a severe neurodevelopmental disease caused by mutations in the X-linked gene encoding for the methyl-CpG-binding protein MeCP2. Here, we report the identification of FOXG1-truncating mutations in two patients affected by the congenital variant of Rett syndrome. FOXG1 encodes a brain-specific transcriptional repressor that is essential for early development of the telencephalon. Molecular analysis revealed that Foxg1 might also share common molecular mechanisms with MeCP2 during neuronal development, exhibiting partially overlapping expression domain in postnatal cortex and neuronal subnuclear localization.
The American Journal of Human Genetics 08/2008; 83(1):89-93. · 10.60 Impact Factor
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Filomena Tiziana Papa,
Maria Antonietta Mencarelli,
Rossella Caselli,
Eleni Katzaki,
Katia Sampieri,
Ilaria Meloni,
Francesca Ariani, Ilaria Longo,
Angela Maggio,
Paolo Balestri,
Salvatore Grosso,
Maria Angela Farnetani,
Rosario Berardi,
Francesca Mari,
Alessandra Renieri
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ABSTRACT: The present report describes a 7-year-old girl with a de novo 3 Mb interstitial deletion of chromosome 14q12, identified by oligo array-CGH. The region is gene poor and contains only five genes two of them, FOXG1B and PRKD1 being deleted also in a previously reported case with a very similar phenotype. Both patients present prominent metopic suture, epicanthic folds, bulbous nasal tip, tented upper lip, everted lower lip and large ears and a clinical course like Rett syndrome, including normal perinatal period, postnatal microcephaly, seizures, and severe mental retardation. FOXG1B (forkhead box G1B) is a very intriguing candidate gene since it is known to promote neuronal progenitor proliferation and to suppress premature neurogenesis and its disruption is reported in a patient with postnatal microcephaly, corpus callosum agenesis, seizures, and severe mental retardation.
American Journal of Medical Genetics Part A 08/2008; 146A(15):1994-8. · 2.39 Impact Factor
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Rossella Caselli,
Maria Antonietta Mencarelli,
Filomena Tiziana Papa,
Francesca Ariani, Ilaria Longo,
Ilaria Meloni,
Giuseppina Vonella,
Maurizio Acampa,
Alberto Auteri,
Stefano Vicari,
Alessandra Orsi,
Giuseppe Hayek,
Alessandra Renieri,
Francesca Mari
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ABSTRACT: Terminal deletions of the long arm of chromosome 7 are well known and are frequently associated with hypotelorism or holoprosencephaly due to the involvement of the SHH gene located in 7q36.3. These deletions are easily detectable with routine subtelomeric MLPA analysis. Deletions affecting a more proximal part of 7q36, namely bands 7q36.1q36.2 are less common, and may be missed by subtelomeric MLPA analysis. We report a 9-year-old girl with a 5.27 Mb deletion in 7q36.1q36.2, and compare her to literature patients proposing a phenotype characterized by mental retardation, unusual facial features, renal hypoplasia and long QT syndrome due to loss of the KCNH2 gene. These characteristics are sufficiently distinct that the syndrome may be diagnosed on clinical grounds.
American Journal of Medical Genetics Part A 06/2008; 146A(9):1195-9. · 2.39 Impact Factor
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Elisa Scala, Ilaria Longo,
Federica Ottimo,
Caterina Speciale,
Katia Sampieri,
Eleni Katzaki,
Rosangela Artuso,
Maria Antonietta Mencarelli,
Tatiana D'Ambrogio,
Giuseppina Vonella,
Michele Zappella,
Giuseppe Hayek,
Agatino Battaglia,
Francesca Mari,
Alessandra Renieri,
Francesca Ariani
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ABSTRACT: Rett syndrome is a neurodevelopmental disorder that represents one of the most common genetic causes of mental retardation in girls. MECP2 point mutations in exons 2-4 account for about 80% of classic Rett cases and for a lower percentage of variant patients. We investigated the genetic cause in 77 mutation-negative Rett patients (33 classic, 31 variant, and 13 Rett-like cases) by searching missed MECP2 defects. DHPLC analysis of exon 1 and MLPA analysis allowed us to identify the defect in 17 Rett patients: one exon 1 point mutation (c.47_57del) in a classic case and 16 MECP2 large deletions (15/33 classic and 1/31 variant cases). One identical intragenic MECP2 deletion, probably due to gonadal mosaicism, was found in two sisters with discordant phenotype: one classic and one "highly functioning" preserved speech variant. This result indicates that other epigenetic or genetic factors, beside MECP2, may contribute to phenotype modulation. Three out of 16 MECP2 deletions extend to the adjacent centromeric IRAK1 gene. A putative involvement of the hemizygosity of this gene in the ossification process is discussed. Finally, results reported here clearly indicate that MECP2 large deletions are a common cause of classic Rett, and MLPA analysis is mandatory in MECP2-negative patients, especially in those more severely affected (P = 0.044).
American Journal of Medical Genetics Part A 01/2008; 143A(23):2775-84. · 2.39 Impact Factor
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Vanna Micheli,
Sylvia Sestini,
Veronica Parri,
Marco Fichera,
Corrado Romano,
Francesca Ariani, Ilaria Longo,
Francesca Mari,
Mirella Bruttini,
Alessandra Renieri,
Ilaria Meloni
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ABSTRACT: Coffin-Lowry syndrome is a semi-dominant condition characterized by severe psychomotor retardation with facial, hand and skeletal malformations resulting from mutations in RSK2 gene, encoding for a serine/threonine kinase. More than 100 different mutations have been identified to date; however, about 50% of clinically diagnosed patients apparently do not have mutations. In order to exclude that these patients have RSK2 mutations missed by standard mutation detection techniques, a rapid and sensitive assay allowing evaluation of RSK2 activity was needed.
RSK2 capacity to phosphorylate a synthetic CREB-peptide in basal and PMA-stimulated conditions was evaluated in lymphoblasts from 3 patients with RSK2 mutations and normal controls.
Patients RSK2 activity is normal in nonstimulated conditions but fails to grow following stimulation. The evaluation of the stimulated/non-stimulated activity ratio demonstrated a statistically significant impairment in patients.
We have set up an assay which allows the identification of even partial alterations of RSK2 activity and seems to give good results also in females with a balanced X-chromosome inactivation and thus with a presumably normal enzymatic activity in about 50% of cells. Moreover, our data seem to confirm previous reports of a potential direct correlation between the level of RSK2 activity and the severity of cognitive impairment.
Clinica Chimica Acta 10/2007; 384(1-2):35-40. · 2.54 Impact Factor
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Katia Sampieri,
Ilaria Meloni,
Elisa Scala,
Francesca Ariani,
Rossella Caselli,
Chiara Pescucci, Ilaria Longo,
Rosangela Artuso,
Mirella Bruttini,
Maria Antonietta Mencarelli,
Caterina Speciale,
Vincenza Causarano,
Giuseppe Hayek,
Michele Zappella,
Alessandra Renieri,
Francesca Mari
[show abstract]
[hide abstract]
ABSTRACT: Rett syndrome is the second most common cause of severe mental retardation in females, with an incidence of approximately 1 out of 10,000 live female births. In addition to the classic form, a number of Rett variants have been described. MECP2 gene mutations are responsible for about 90% of classic cases and for a lower percentage of variant cases. Recently, CDKL5 mutations have been identified in the early onset seizures variant and other atypical Rett patients. While the high percentage of MECP2 mutations in classic patients supports the hypothesis of a single disease gene, the low frequency of mutated variant cases suggests genetic heterogeneity. Since 1998, we have performed clinical evaluation and molecular analysis of a large number of Italian Rett patients. The Italian Rett Syndrome (RTT) database has been developed to share data and samples of our RTT collection with the scientific community (http://www.biobank.unisi.it). This is the first RTT database that has been connected with a biobank. It allows the user to immediately visualize the list of available RTT samples and, using the "Search by" tool, to rapidly select those with specific clinical and molecular features. By contacting bank curators, users can request the samples of interest for their studies. This database encourages collaboration projects with clinicians and researchers from around the world and provides important resources that will help to better define the pathogenic mechanisms underlying Rett syndrome.
Human Mutation 05/2007; 28(4):329-35. · 5.69 Impact Factor
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Eleni Katzaki,
Chiara Pescucci,
Vera Uliana,
Filomena Tiziana Papa,
Francesca Ariani,
Ilaria Meloni,
Manuela Priolo,
Angelo Selicorni,
Donatella Milani,
Rita Fischetto,
Maria Elena Celle,
Rita Grasso,
Bruno Dallapiccola,
Francesco Brancati,
Marta Bordignon,
Romano Tenconi,
Antonio Federico,
Francesca Mari,
Alessandra Renieri, Ilaria Longo
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ABSTRACT: Cohen syndrome is an autosomal recessive disorder with variability in the clinical manifestations, characterized by developmental delay, visual disability, facial dysmorphisms and intermittent neutropenia. We described a cohort of 10 patients affected by Cohen syndrome from nine Italian families ranging from 5 to 52 years at assessment. Characteristic age related facial changes were well documented. Visual anomalies, namely retinopathy and myopia, were present in 9/10 patients (retinopathy in 9/10 and myopia in 8/10). Truncal obesity has been described in all patients older than 6 years (8/8). DNA samples from all patients were analyzed for mutations in COH1 by DHPLC. We detected 15 COH1 alterations most of them were truncating mutations, only one being a missense change. Partial gene deletions have been found in two families. Most mutations were private. Two were already reported in the literature just once. A single base deletion leading to p.T3708fs3769, never reported before, was found in three apparently unrelated families deriving from a restricted area of the Veneto's lowland, between Padova town and Tagliamento river, in heterozygous state. Given the geographical conformation of this region, which is neither geographically or culturally isolated, a recent origin of the mutation could be hypothesized.
Journal of Human Genetics 02/2007; 52(12):1011-7. · 2.57 Impact Factor
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ABSTRACT: To assess the influence of optineurin in the more common high-tension, primary open-angle glaucoma (POAG).
Eighteen sporadic cases and 35 probands from 35 familial cases, including three families with one member having normal-tension glaucoma (NTG), were enrolled. Using transgenomic WAVE denaturing high-performance liquid chromatography (DHPLC), all coding portion of the optineurin gene (from exon 4 to exon 16) was analyzed. Samples displaying an altered elution profile were sequenced to confirm and identify sequence variants. Exon 4 containing the previously reported p.E50K (Glu50Lys) recurrent mutation (covering 13% of normotensive cases) was entirely sequenced.
We did not detect the mutation p.E50K, and we did not find any other pathogenic mutation. A putative splice-site mutation was detected in one family. Extension of segregation analysis to additional family members and mRNA investigation failed to establish a certain involvement of this mutation with the disease. We detected a number of common polymorphisms, including the previously reported p.M98K (Met98Lys) variant.
In this population, mutations in the optineurin gene are not associated with adult-onset primary POAG.
Albrecht von Graæes Archiv für Ophthalmologie 10/2006; 244(9):1077-82. · 2.17 Impact Factor
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Ilaria Longo,
Elisa Scala,
Francesca Mari,
Rossella Caselli,
Chiara Pescucci,
Maria Antonietta Mencarelli,
Caterina Speciale,
Marisa Giani,
Elena Bresin,
Domenica Angela Caringella,
Zvi-Uri Borochowitz,
Komudi Siriwardena,
Ingrid Winship,
Alessandra Renieri,
Ilaria Meloni
[show abstract]
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ABSTRACT: Alport syndrome (ATS) is a progressive inherited nephropathy characterized by irregular thinning, thickening and splitting of the glomerular basement membrane (GBM) often associated with hearing loss and ocular symptoms. ATS has been shown to be caused by COL4A5 mutations in its X-linked form and by COL4A3 and COL4A4 mutations in its autosomal forms.
Five families with a suspicion of ATS were investigated both from a clinical and molecular point of view. COL4A3 and COL4A4 genes were analysed by DHPLC. Automated sequencing was performed to identify the underlying mutation.
Molecular analysis indicated that in all 5 cases the correct diagnosis was autosomal recessive ATS. In three families in which parental consanguinity clearly pinpointed to autosomal recessive ATS, we found COL4A4 homozygous mutations in two of them and COL4A3 homozygous mutation in the other one. In the remaining two families a differential diagnosis including X-linked ATS, autosomal recessive ATS and thin basement membrane nephropathy was considered. The molecular analysis demonstrated that the probands were genetic compounds for two different mutations in the COL4A4 gene pinpointing to the correct diagnosis of autosomal recessive ATS.
A clinical evaluation of probands and their relatives of the five families carrying mutations in either the COL4A3 or the COL4A4 gene was carried out to underline the natural history of the autosomal recessive ATS. In addition, this paper stresses the complexity of the clinics and genetics of ATS and how a correct diagnosis is based on a combination of: (i) an in-depth clinical investigation; (ii) a detailed formal genetic analysis; (iii) a correct technical choice of the gene to be investigated; (iv) a correct technical choice of the family member to be included in the mutational screening. A correct diagnosis is the basis for an appropriate genetic counselling dealing with both the correct prognosis and the accurate recurrence risk for the patients and family members.
Nephrology Dialysis Transplantation 04/2006; 21(3):665-71. · 3.40 Impact Factor
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Francesca Mari,
Sara Azimonti,
Ilaria Bertani,
Fabrizio Bolognese,
Elena Colombo,
Rossella Caselli,
Elisa Scala, Ilaria Longo,
Salvatore Grosso,
Chiara Pescucci,
Francesca Ariani,
Giuseppe Hayek,
Paolo Balestri,
Anna Bergo,
Gianfranco Badaracco,
Michele Zappella,
Vania Broccoli,
Alessandra Renieri,
Charlotte Kilstrup-Nielsen,
Nicoletta Landsberger
[show abstract]
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ABSTRACT: Rett syndrome (RTT) is a severe neurodevelopmental disorder almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Most patients affected by classic RTT and a smaller percentage of patients with the milder form 'preserved speech variant' have either point mutations or deletions/duplications in the MECP2 gene. Recently, mutations in the CDKL5 gene, coding for a putative kinase, have been found in female patients with a phenotype overlapping with that of RTT. Here, we report two patients with the early seizure variant of RTT, bearing two novel CDKL5 truncating mutations, strengthening the correlation between CDKL5 and RTT. Considering the similar phenotypes caused by mutations in MECP2 and CDKL5, it has been suggested that the two genes play a role in common pathogenic processes. We show here that CDKL5 is a nuclear protein whose expression in the nervous system overlaps with that of MeCP2, during neural maturation and synaptogenesis. Importantly, we demonstrate that MeCP2 and CDKL5 interact both in vivo and in vitro and that CDKL5 is indeed a kinase, which is able to phosphorylate itself and to mediate MeCP2 phosphorylation, suggesting that they belong to the same molecular pathway. Furthermore, this paper contributes to the clarification of the phenotype associated with CDKL5 mutations and indicates that CDKL5 should be analyzed in each patient showing a clinical course similar to RTT but characterized by a lack of an early normal period due to the presence of seizures.
Human Molecular Genetics 08/2005; 14(14):1935-46. · 7.64 Impact Factor
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Giovanni M Frascà,
Andrea Onetti-Muda,
Francesca Mari, Ilaria Longo,
Elisa Scala,
Chiara Pescucci,
Dario Roccatello,
Mirella Alpa,
Rosanna Coppo,
Giovanni Li Volti,
Sandro Feriozzi,
Franco Bergesio,
Francesco P Schena,
Alessandra Renieri
[show abstract]
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ABSTRACT: Thin glomerular basement membrane disease (TBMD) is a nephropathy defined by diffuse thinning of the glomerular basement membrane (GBM) at electron microscopy examination, without the alterations of Alport's syndrome (ATS). It is known that many patients with TBMD have a type IV collagen disorder and that the disease occasionally may be progressive. This study investigated 51 patients with the morphological diagnosis of TBMD lacking any sign of ATS, with the aim of defining the prevalence of type IV collagen mutations and the course of the disease.
Patients were investigated as follows: (a) clinical picture and family investigation; (b) renal biopsy findings; (c) immunohistochemical study of renal tissue for collagen IV alpha-chains; (d) pedigree reconstruction and molecular investigations in genes encoding type IV collagen chains, when DNA samples were available; and (e) follow-up data.
Renal biopsy analysis revealed no light microscopy changes in 27 patients and minimal abnormalities in the remainder. Global glomerular sclerosis was found in seven cases and superimposed mesangial immunoglobulin-A deposits in four. Normal staining of GBM for alpha(IV) chains was observed in all but one patient, where alpha5(IV) was absent and molecular investigation revealed a COL4A5 mutation. Five out of 25 cases had a mutation in the COL4A3/COL4A4 genes. Eight out of 38 patients followed up for 12-240 months (21%) showed signs of disease progression or hypertension.
This study confirms that a considerable proportion of patients with TBMD have a type IV collagen disorder and that this lesion is not always benign. Thus, families should be investigated carefully whenever possible and patients and affected relatives should be examined periodically for signs of disease progression.
Nephrology Dialysis Transplantation 04/2005; 20(3):545-51. · 3.40 Impact Factor
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ABSTRACT: Mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2) are found in 70-80% of cases of classical Rett syndrome (RTT) and in about 50% of cases of preserved speech variant (PSV). This high percentage of MECP2 mutations, especially in classical RTT cases, suggests that another major RTT locus is unlikely. Missed mutations may be due to the limited sensitivity of the methodology used for mutation scanning and/or the presence of intronic mutations. In a double-copy gene, such as MECP2 in females, current methodologies (e.g., DGGE, SSCP, DHPLC, direct sequencing) are prone to miss gross rearrangements. Three previous reports during 2001-2003 have shown the presence of large deletions in a fraction of MECP2-negative classical RTT patients. We developed a reliable, single tube, quantitative PCR assay for rapid determination of MECP2 gene dosage. This method involves a multiplex reaction using a FAM labeled TaqMan probe with a TAMRA quencher derived from MECP2 exon 4 and two primers derived from the same exon and RNAaseP as an internal reference. The copy number of the MECP2 gene was determined by the comparative threshold cycle method (ddCt). Each sample was run in quadruplicate. We validated this assay through the analysis of 30 healthy controls (15 female and 15 male) and we then applied this method to eight classical RTT and six PSV patients, all negative for MECP2 mutations. We identified gross rearrangements in two patients: a deletion in a classical RTT patient and a duplication in a PSV patient. Our results confirm that a fraction of MECP2-negative RTT cases have MECP2 gross rearrangements and we propose real-time quantitative PCR as a simple and reliable method for routine screening of MECP2 in addition to DHPLC analysis.
Human Mutation 09/2004; 24(2):172-7. · 5.69 Impact Factor
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Ilaria Longo,
Luisa Russo,
Ilaria Meloni,
Iolanda Ricci,
Francesca Ariani,
Chiara Pescucci,
Carmela Tiziana Giordano,
Roberto Canitano,
Giuseppe Hayek,
Michele Zappella,
Giovanni Neri,
Alessandra Renieri,
Fiorella Gurrieri
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ABSTRACT: Autism and Rett syndrome, a severe neurological disorder with autistic behavior, are classified as separate disorders on clinical and etiological ground. Rett syndrome is a monogenic X-linked dominant condition due to de novo mutations in the MECP2 gene, whereas autism is a neurodevelopmental and behavioral disorder with complex genetic basis. Maternally inherited duplications on 15q11-q13 are found in a fraction of autistic children suggesting that an abnormal dosage of gene(s) within this region might cause susceptibility to autism. Now we show that three Rett patients are carriers of both a MECP2 mutation and a 15q11-q13 rearrangement, suggesting that there might be a relationship between autism-related genes and the MECP2 gene.
European Journal of HumanGenetics 09/2004; 12(8):682-5. · 4.40 Impact Factor
