-
[show abstract]
[hide abstract]
ABSTRACT: Autism is a strong genetic disorder, with an estimated heritability greater than 90%. Nonetheless, its specific genetic aetiology remains largely unknown. Autism is associated with epilepsy in early childhood and epilepsy occurs in 10-30% of individuals with autism. Here we report the case of a woman affected by a severe epileptic disorder with an onset at 14 years old. She is affected by a cryptogenetic focal epilepsy with complex partial (psychomotor) and secondarily generalized tonic-clonic seizures, which are drug resistant. The woman is married to a healthy man and has six children: two girls are healthy, a girl and two boys are affected by autism while one boy shows partial seizures. The three children with autism show moderate mental retardation and an EEG with no epileptiform alterations. The child with epileptic seizures shows an asymmetric EEG that is not necessarily pathological. In this family, no chromosomal rearrangements were detected by means of classical cytogenetic analyses. The presence of FRAXA alterations and of microdeletions of the 15q11-q13 chromosome region were also excluded. A genome-wide linkage analysis using microsatellite markers revealed several chromosome regions as possible susceptibility loci.
Brain research bulletin 02/2010; 82(1-2):25-8. · 2.18 Impact Factor
-
S G M Piccirillo,
R Combi,
L Cajola,
A Patrizi,
S Redaelli,
A Bentivegna,
S Baronchelli,
G Maira,
B Pollo,
A Mangiola,
F DiMeco, L Dalprà,
A L Vescovi
[show abstract]
[hide abstract]
ABSTRACT: Glioblastomas (GBMs) contain transformed, self-maintaining, multipotent, tumour-initiating cancer stem cells, whose identification has radically changed our perspective on the physiology of these tumours. Currently, it is unknown whether multiple types of transformed precursors, which display alternative sets of the complement of properties of true cancer stem cells, can be found in a GBM. If different subsets of such cancer stem-like cells (CSCs) do exist, they might represent distinct cell targets, with a differential therapeutic importance, also depending on their characteristics and lineage relationship. Here, we report the presence of two types of CSCs within different regions of the same human GBM. Cytogenetic and molecular analysis shows that the two types of CSCs bear quite diverse tumorigenic potential and distinct genetic anomalies, and, yet, derive from common ancestor cells. This provides critical information to unravel the development of CSCs and the key molecular/genetic components underpinning tumorigenicity in human GBMs.
Oncogene 04/2009; 28(15):1807-11. · 6.37 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Studies attempting to precisely define the range of fragile mental retardation 1 (FMR1) expansions and its inf luence in premature ovarian failure (POF) manifestation are partially lacking. To this aim, we evaluated a large cohort of POF patients for the size and, in selected cases, for the sequence of the CGG expansion. Furthermore, the correlation between POF and X-inactivation was investigated in FRAXA families.
By fluorescent PCR, 190 POF and 200 control women were sized for the CGG tract; some subjects were also characterized by sequencing and for the FMR1 activation ratio.
We found a significant association (19/190, 10%, P < 1 x 10(-6)) between POF and FMR1 premutation (range 63-163 repeats) and a significant enrichment (9/190, 4.7%, P = 0.021) of POF carriers of intermediate expansions (range 41-58 repeats). Interestingly, intermediate alleles were entirely composed of CGG repeats. Furthermore, the analysis of three pairs of siblings with similar FMR1 expansions and discordant for the POF phenotype showed a direct correlation between the expression of the intermediate/premutated allele and POF manifestation. The results obtained strengthen the correlation between FMR1 expansion and POF and suggest that the manifestation of the ovarian dysfunction could be influenced both by the pattern of interruption of the CGG repeat and by X-inactivation.
Human Reproduction 05/2006; 21(4):952-7. · 4.47 Impact Factor
-
S Bione,
F Rizzolio,
C Sala,
R Ricotti,
M Goegan,
M C Manzini,
R Battaglia,
A Marozzi,
W Vegetti, L Dalprà,
P G Crosignani,
E Ginelli,
R Nappi,
S Bernabini,
V Bruni,
F Torricelli,
O Zuffardi,
D Toniolo
[show abstract]
[hide abstract]
ABSTRACT: Balanced X;autosome translocations interrupting the 'critical region' of the long arm of the human X chromosome are often associated with premature ovarian failure (POF). However, the mechanisms leading to X-linked ovarian dysfunction are largely unknown, as the majority of the X chromosome breakpoints have been mapped to gene-free genomic regions. A few genes have been found to be interrupted, but their role has never been clarified.
By fine mapping of the X chromosome breakpoint of an X;autosome balanced translocation, we identified a new interrupted gene, POF1B. We performed a mutation analysis of POF1B and of another gene previously identified, DACH2, localized approximately 700 kb distal in Xq21, in a cohort of >200 Italian POF patients. Rare mutations were found in patients in both genes.
Our findings could not demonstrate any involvement of POF1B, but suggest that rare mutations in the DACH2 gene may have a role in the POF phenotype.
Human Reproduction 12/2004; 19(12):2759-66. · 4.47 Impact Factor
-
A Sensi,
S Cavani,
N Villa,
M G Pomponi,
A Fogli,
F Gualandi,
M Grasso,
E Sala,
R Pietrobono,
F Baldinotti, [......],
S Rossi,
S Gallone,
C Bellini,
G Neri,
E Martinoli,
P Simi, L Dalprà,
M Genuardi,
F Dagna-Bricarelli,
E Calzolari
[show abstract]
[hide abstract]
ABSTRACT: The risk of uniparental disomy (UPD) occurrence associated with the prenatal finding of balanced nonhomologous Robertsonian translocations (NHRTs) has been estimated only on limited empirical data. The aim of the study was to verify the estimate of the general risk, to get narrower confidence intervals by cumulating the data and to obtain risk estimates for specific translocation types.
We tested for UPD 160 prenatal specimens referred to the participant centers after the cytogenetic finding of NHRT.
One case of upd(14)mat was found, associated with a 45,XX,der(14;22)mat fetal karyotype. The general empirical risk of UPD occurrence in NHRT carrier fetuses, corrected for the actual number of chromosomes analyzed, was 0.76% (95% CI 0.02-4.25%). Cumulative data with previous studies gives a general risk of UPD associated with NHRT of 0.80% (95% CI 0.17-2.34%). The UPD risk for the specific NHRT der(13;14) did not significantly differ from that of the other NHRTs taken together.
The present survey confirms the previously estimated risk of occurrence of UPD in offspring of NHRT carriers as a low, but not negligible risk, worth being investigated in prenatal diagnosis.
Prenatal Diagnosis 09/2004; 24(8):647-52. · 2.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Autosomal dominant
nocturnal frontal lobe epilepsy
(ADNFLE) is an idiopathic
epilepsy, with a spectrum of clinical
manifestations, ranging from
brief, stereotyped, sudden arousals
to more complex dystonic–dyskinetic
seizures. Video–polysomnography
allows a correct differential
diagnosis. There is no difference
between sporadic nocturnal frontal
lobe epilepsy (NFLE) and ADNFLE
in the clinical and neurophysiological
findings. ADNFLE is the first idiopathic
epilepsy for which a genetic
basis has been identified. Mutations
have been found in two
genes (CHRNA4 and CHRNB2)
coding for neuronal nicotinic receptor
subunits (4 and 2, respectively).
Contrasting data have been
reported on the effect of these mutations
on the functionality of the
receptor.Moreover, the incomplete
data on the neuronal network/s in
which this receptor is involved,
make difficult the understanding of
the genotype–phenotype correlation.
This is an overview on the
clinical and genetic aspects of ADNFLE
including a discussion of
some open questions on the role of
the neuronal nicotinic receptor
subunit mutations in the pathogenesis
of this form of epilepsy.
Journal of Neurology 07/2004; 251(8):923-934. · 3.47 Impact Factor
-
Journal of Medical Genetics 09/2002; 39(8):e42. · 6.36 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Premature ovarian failure (POF) is a secondary hypergonadotrophic amenorrhoea affecting 1-3% of females, whose aetiology is almost unknown. However, inhibin alpha gene (INHalpha) has recently been indicated as candidate in POF pathogenesis.
We analysed patients affected by POF (n = 157) for the missense mutation (769G-->A transition) in the exon 2 of the INHalpha gene. The same analysis was carried out on early menopause (EM) (n = 36) and primary amenorrhoea (n = 12) patients.
The incidence of the mutation was significantly more frequent within both POF (7/157, 4.5%) (Fisher's exact test, P = 0.030) and primary amenorrhoea (3/12, 25%) (Fisher's exact test, P < 0.001) patients, compared with the control population of women (0/100), who experienced physiological menopause. No mutation was found in EM patients. Furthermore, the likelihood of finding the mutation was statistically significant in familial (5/65; 7.7%) (Fisher's exact test, P < 0.01) but not in sporadic (2/92; 2.2%) (Fisher's exact test, P = not significant) POF, compared with the control group. The analysis of pedigrees showing the inheritance of the 769G-->A mutation and POF strengthens the concept of the disease heterogeneity, since the POF phenotype was not always associated with the mutation. Moreover, a higher prevalence of the C allele of a single nucleotide polymorphism (129C-->T), located in the 5'-UTR of the INHalpha gene, was observed in POF patients (80.3%) than in the control group (66.7%) (Fisher's exact test, P = 0.014).
These data strengthen the concept of the INHalpha gene as a candidate for ovarian failure.
Human Reproduction 07/2002; 17(7):1741-5. · 4.47 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A patient with microbrachycephaly, high forehead, long philtrum, thin upper lip, downturned corners of the mouth, low set ears with overlapping helix, fifth-finger clinodactyly, small hands and feet, bilateral transverse palmar crease, low total finger ridge count, hypotonia, severe growth and psychomotor delay, mild hypoplasia of corpus callosum, and Arnold-Chiari type 1 malformation is reported. The karyotype showed 46, XY, del(1)(q23q31.2). Coagulation factor V (F5, 1q23) and coagulation factor XIII (F13B, 1q31-q32.1) levels were normal. As expected, antithrombin III (AT3, 1q23-q25.1) serum level and activity were half of normal. We performed a review of the literature on proximal and intermediate deletion 1q syndrome, and we hypothesize the existence of only one 1q interstitial deletion syndrome, clinically characterized by ATIII deficiency.
American Journal of Medical Genetics 01/2002; 104(4):282-6.
-
[show abstract]
[hide abstract]
ABSTRACT: The identification of small supernumerary marker chromosomes (SMCs) and the elucidation of their clinical significance remain two of the problems in classical human cytogenetics. We observed a small supernumerary ring in amniotic fluid cell cultures and identified its origin as r(2)(p10q11.2) and its extent by means of fluorescent in situ hybridisation (FISH). Uniparental disomy (UPD) was excluded by microsatellite analysis using polymorphic markers localised in the same region. On the basis of normal ultrasonographic checks, the patient decided to continue the pregnancy. A normal female was delivered at term and subsequent neonatal follow-ups confirmed the normal phenotype and development. In the present case, genetic counselling was not helpful because of the absence of reference cases. Detailed characterisation made it possible to correlate the normal baby phenotype with the trisomic 2p10-2q11.2 genomic region. Further molecular cytogenetic investigations of SMCs classified by DNA content and pregnancy outcome data should improve genetic counselling and risk evaluation.
Prenatal Diagnosis 11/2001; 21(10):801-5. · 2.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Genes coding for the alpha5, alpha3, and beta4 subunits (CHRNA5, CHRNA3, and CHRNB4) of the neuronal nicotinic acetylcholine receptors (nAChRs) are clustered on chromosome 15q24. Linkage of this chromosomal region to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), an idiopathic partial epilepsy, was reported in one family. Moreover, mutations in other neuronal nAChR subunit genes coding for the alpha4 (CHRNA4) and the beta2 (CHRNB2) subunits were associated with ADNFLE. Apart from the exon-intron structure of CHRNA3, the genomic organization of this gene cluster was unknown, making comprehensive mutational analyses impossible. The genomic structure of CHRNA5 and CHRNB4 is here reported. Moreover, two hitherto unknown introns were identified within the 3' untranslated region of CHRNA3, causing a partial tail-to-tail overlap with CHRNA5. Four novel intragenic polymorphisms were identified and characterized in the cluster.
Journal of Human Genetics 02/2001; 46(11):640-8. · 2.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A new polymorphism in intron 1 of the neuronal nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4) was identified. It consists of a G to T substitution located in the downstream flanking region of a previously reported CA repeat marker. This polymorphism whose frequency is about six percent in a control population occurs near the 3' end of the reverse primer generally used to type the CA repeat marker. Data are presented showing that the newly identified polymorphism causes erroneous genotyping of the CA repeat marker which can alter the results of linkage analysis for CHRNA4. The use of a different reverse primer located 34 nt downstream of the published sequence overcame errors in genotyping and identified two novel alleles of the CA repeat marker. Re-typing of the marker with the new proposed primer pair in a Caucasian control population of 107 unrelated individuals was also performed
Molecular and Cellular Probes 01/2001; 14(6):373-80. · 2.08 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: High-resolution cytogenetic analysis of a large number of women with premature ovarian failure (POF) identified six patients carrying different Xq chromosome rearrangements. The patients (one familial and five sporadic cases) were negative for Turner's stigmata and experienced a variable onset of menopause. Microsatellite analysis and fluorescent in situ hybridization (FISH) were used to define the origin and precise extension of the Xq anomalies. All of the patients had a Xq chromosome deletion as the common chromosomal abnormality, which was the only event in three cases and was associated with partial Xp or 9p trisomies in the remaining three. Two of the Xq chromosome deletions were terminal with breakpoints at Xq26.2 and Xq21.2, and one interstitial with breakpoints at Xq23 and Xq28. In all three cases, the del(X)s retained Xp and Xq specific telomeric sequences. One patient carries a psu dic(X) with the deletion at Xq22.2 or Xq22.3; the other two [carrying (X;X) and (X;9) unbalanced translocations, respectively] showed terminal deletions with the breakpoint at Xq22 within the DIAPH2 gene. Furthermore, the rearranged X chromosomes were almost totally inactivated, and the extent of the Xq deletions did not correlate with the timing of POF. In agreement with previous results, these findings suggest that the deletion of a restricted Xq region may be responsible for the POF phenotype. Our analysis indicates that this region extends from approximately Xq26.2 (between markers DXS8074 and HIGMI) to Xq28 (between markers DXS 1113 and ALD) and covers approximately 22 Mb of DNA. These data may provide a starting point for the identification of the gene(s) responsible for ovarian development and folliculogenesis.
Human Genetics 11/2000; 107(4):304-11. · 5.07 Impact Factor
-
Journal of Medical Genetics 09/2000; 37(8):612-5. · 6.36 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The chromosome 15q24 region, containing the CHRNA3/A5/B4 gene cluster, coding for the alpha3, alpha5 and beta4 subunits of neuronal nicotinic acetylcholine receptors, has been reported to be linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in one family. However, nor the gene nor the mutation involved have been identified. We report the refined mapping of CHRNA3/A5/B4 cluster. Segregation analyses of CHRNA3/A5/B4 polymorphisms in families showing recombinations for 15q24 G¿en¿ethon STR markers allowed to position the cluster in a 0.6 cM interval, between STRs D15S1027 and D15S1005. This location is external to the 15q24-ADNFLE-linked region, therefore excluding the involvement of this cluster in the pathogenesis of ADNFLE in the 15q24-linked family. Moreover, these data provide more precise information for further linkage studies.
Neuroreport 08/2000; 11(10):2097-101. · 1.66 Impact Factor
-
M Miozzo, L Dalprà,
P Riva,
M Volontà,
F Macciardi,
S Pericotti,
M G Tibiletti,
M Cerati,
K Rohde,
L Larizza,
A M Fuhrman Conti
[show abstract]
[hide abstract]
ABSTRACT: Previous cytogenetic/FISH data have demonstrated 1p36 deletions in a relapsing familial clivus chordoma developed by a patient who has 2 daughters, respectively affected with childhood astrocytoma and clivus chordoma. Using an approach that combined the LOH (loss of heterozygosity) study of the father chordoma and the daughter astrocytoma and a segregation analysis from parents to sibs using 17 CA-repeats spanning 1p36.32-1p36.11, we mapped the cancer susceptibility locus in this family to the 1p36 region. The LOH and haplotype information was elaborated using a pairwise linkage analysis that gave a maximum lod score of 1.2. Additional LOH data relating to 6 sporadic chordomas allowed us to define an SRO (the smallest region of overlapping loss) of about 25 cM from D1S2845 (1p36.31) to D1S2728 (1p36.13). Our overall findings converge on mapping to 1p36 a tumor-suppressor gene involved in familial and sporadic chordoma.
International Journal of Cancer 08/2000; 87(1):68-72. · 5.44 Impact Factor
-
W Vegetti,
A Marozzi,
E Manfredini,
G Testa,
F Alagna,
A Nicolosi,
I Caliari,
M Taborelli,
M G Tibiletti, L Dalprà,
P G Crosignani
[show abstract]
[hide abstract]
ABSTRACT: Secondary amenorrhoea with elevated gonadotrophins occurring under the age of 40 (premature ovarian failure (POF)), and at the age between 41 and 44 years (early menopause (EM)), respectively, affects 1-2% and 5% of women in the general population. Objective of this study was to evaluate the prevalence of familial cases of POF and EM and to assess the clinical and genetic characteristics of these patients. One hundred and sixty women with idiopathic secondary amenorrhoea before the age of 45 and serum follicle-stimulating hormone (FSH) levels greater than or equal to 40 IU/l were included in the study. Tests performed on patients included complete medical history, pedigree's analysis, clinical pelvic examination, gonadotrophins and thyroid assessment, chromosomal analysis. The 160 patients included in the study showed idiopathic POF (n=130) or EM (n=30). Following pedigree assessment, we were able to identify an incidence of familial cases of 28.5% in the POF group (n=37) and of 50% in the EM group (n=15). POF and EM condition were often present in the same family. There were no differences between POF and EM patients and between familial and sporadic cases regarding age at menarche, personal history, gynaecological history, weight, height and diet habits. There was a statistically significant difference between sporadic and familial cases in age at POF onset: 32.0+/-7.3 years (12-40) compared to 35. 0+/-5.8 (18-40), respectively (P<0.05). The POF and EM families identified showed two or more affected females and transmission through either maternal or paternal relatives; in four families both maternal and paternal transmission was observed. This study suggests that idiopathic POF and EM conditions, differing only in age of menopause onset, may represent a variable expression of the same genetic disease. The different age of menopause onset in these patients may be explained by genetic heterogeneity and/or by different environmental factors. Our results indicate a high rate of familial transmission of the condition. Pedigree's analysis suggests an autosomal or an X-linked dominant sex-limited pattern of inheritance for POF and EM.
Molecular and Cellular Endocrinology 03/2000; 161(1-2):53-7. · 4.19 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A total of 106 women affected by premature ovarian failure (POF) were evaluated for fragile X (FRAXA) premutation. The POF patients were classified as having a familial condition (33 women), at least one relative with early menopause (12 women), or a sporadic condition (61 women). The FRAXA premutation was only detected in patients with familial (four out of 33) or sporadic POF (two out of 61). In general, the results obtained indicated that the prevalence [six out of 106, 6%, 95% confidence interval (CI) 3-11%] of FRAXA premutation is significantly higher in women affected by POF than expected (P = 1.24x10(-3)), suggesting a phenotype consequence of the premutation alleles. This relationship is more convincingly derived from the observation in two analysed pedigrees of a co-segregation between FRAXA and POF. These findings suggest a possible involvement of premutated alleles in ovarian failure, and indicate the utility of POF families screening for FRAXA premutation in order to prevent the transmission of mental retardation syndrome.
Human Reproduction 01/2000; 15(1):197-202. · 4.47 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Genetic factors may influence the timing of menopause. Premature ovarian failure (POF) has recently been identified as a genetic entity, but no genetic data are available on early menopause (EM). We investigated 36 patients with EM (age of menopause between 40 and 45 years of age) using cytogenetic and pedigree analysis. In 30 patients of this study the EM was idiopathic and 15 subjects (50%) had a familial condition of EM or POF. Pedigree analysis revealed a dominant pattern of inheritance of EM through maternal or paternal relatives. Our data reveal that POF and EM patients show the same genetic features and we postulate that these conditions may be a variable expression of the same genetic disease.
Human Reproduction 12/1999; 14(11):2731-4. · 4.47 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 41 patients (19 sporadic and 22 familial) affected by autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) were analyzed for the presence of two mutations (Ser252Phe, 776ins3) in the CHRNA4 gene, reported to be associated with this disease. Electroclinical findings of sporadic forms were indistinguishable from familial ones. In none of the patients, these mutations were found by dot blot analysis with allele specific oligonucleotides. These data, obtained on the largest group so far studied, suggest the rarity of the reported mutations.
Sleep 09/1999; 22(5):637-9. · 5.05 Impact Factor
