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E Bellone

Publications and source records attributed to E Bellone.

At least 19 recordsLinked to original sources
PubMed2005

An abnormal mRNA produced by a novel PMP22 splice site mutation associated with HNPP.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant, demyelinating neuropathy. Point mutations in the PMP22 gene are a rare cause of HNPP. A novel PMP22 splice site mutation (c.179+1 G-->C) is reported in an HNPP family. By reverse transcriptase-polymerase chain reaction experiments, this mutation was shown to cause the synthesis of an abnormal mRNA in which a premature stop codon probably produces a truncated non-functional protein.

Adult↗
PubMed2004

A novel mutation of GDAP1 associated with Charcot-Marie-Tooth disease in three Italian families: evidence for a founder effect.

BACKGROUND: Mutations in a gene encoding a novel protein of unknown function-the ganglioside-induced differentiation-associated protein 1 gene (GDAP1)-are associated with the autosomal recessive Charcot-Marie-Tooth disease type 4A (CMT4A). OBJECTIVE: To investigate the role of GDAP1 mutations in causing autosomal recessive neuropathies in an Italian population. METHODS AND RESULTS: 76 patients with severe early onset polyneuropathy and possible autosomal recessive inheritance were screened for mutations. A T>G transversion (c.347 T>G) at codon 116 (M116R) was detected in four affected subjects from three apparently unrelated families. All patients had early onset of disease with pronounced foot deformities and impaired walking. Neurophysiological studies showed an extremely variable expression. Sural nerve biopsies revealed signs of both de-remyelination and axonal impairment, the most prominent feature being a severe loss of larger fibres. Haplotype analysis of the GDAP1 locus demonstrated a common disease haplotype. CONCLUSIONS: The association of the mutation with a common haplotype suggested a common ancestor.

Adolescent↗
PubMed2004

A novel mutation of myelin protein zero associated with an axonal form of Charcot-Marie-Tooth disease.

OBJECTIVE: To report a new mutation in the MPZ gene which encodes myelin protein zero (P0), associated with an axonal form of Charcot-Marie-Tooth disease (CMT). METHODS: Three patients from an Italian family with a mild, late onset axonal peripheral neuropathy are described clinically and electrophysiologically. To detect point mutation in MPZ gene the whole coding sequence was examined. The structure of the mutated protein was investigated using the three dimensional model of P0. RESULTS: All patients showed a relatively mild CMT phenotype characterised by late onset and heterogeneity of the clinical and electrophysiological features. Molecular analysis demonstrated a novel heterozygous T/A transversion in the exon 3 of MPZ gene that predicts an Asp109Glu amino acid substitution in the extracellular domain of the P0. Asp109 is found at the protein surface, on beta strand E, in the interior of the P0 tetramer. CONCLUSIONS: The identification of Asp109Glu mutation confirms the pivotal role of P0 in axonal neuropathies and stresses the phenotypic heterogeneity associated with MPZ mutations. This study suggests the value of screening for MPZ mutations in CMT family members with minor clinical and electrophysiological signs of peripheral neuropathy.

Aged↗
PubMed2001

The D355V mutation decreases EGR2 binding to an element within the Cx32 promoter.

Mutations in the early growth response 2 (EGR2) gene are associated with some forms of Charcot--Marie--Tooth disease (CMT) and other demyelinating neuropathies. These mutations modify the EGR2 binding to specific DNA sequences suggesting a role in the transcriptional control of myelination-specific genes. Here we show that the D355V mutation, associated with a CMT case combining axonal and demyelinating abnormalities, reduces three times the affinity of EGR2 to its consensus sequence and ten times its affinity to a sequence in the human Cx32 promoter. These findings could indicate that this EGR2 mutation leads to the development of CMT1 through the transcriptional deregulation of Cx32 gene.

Adolescent↗
PubMed2001

No evidence of association between CAG expansions and essential tremor in a large cohort of Italian patients.

Essential tremor (ET) is one of the most common movement disorders. However the pathogenesis is as yet unknown, although a genetic cause has long been recognised. Clinical and molecular evidences suggested that the ET gene might contain a CAG expanded region. In a cohort of Italian ET patients Repeat Expansion Detection (RED) approach did not demonstrate large CAG expansions. We extended the study towards specific targets: the channel proteins hSKCa3 and CACNL1A4. Direct assessment of CAG stretches within these two genes did not demonstrate any CAG expansion in affected subjects. Also a case-control analysis failed to reveal any evidence of association, thus excluding these genes as a cause of ET.

Aged↗
PubMed2001

Clinical and genetic study of essential tremor in the Italian population.

Essential tremor (ET) is one of the most common movement disorders. The pathogenesis is as yet unknown, although a genetic cause has long been recognised. Clinical and molecular evidence suggested that the ET gene contains a CAG expanded region. We examined a cohort of 240 Italian ET patients, classified as familial (193 cases) and sporadic (47 cases). The clinical manifestations of ET patients confirmed that the disorder is characterised by a large phenotypic variability. Repeat expansion detection (RED) approach did not demonstrate large CAG expansions. Six families were genotyped with 12 microsatellites markers of 2p and 3q regions and analysed according to parametrical methods. Lod scores values obtained in these families excluded the association of ET with 2p and 3q loci. Our findings confirm the presence of genetic heterogeneity and suggest that at least a third locus is involved in the pathogenesis of familial essential tremor.

Adolescent↗
PubMed2000

Family and molecular data for a fine analysis of age at onset in Huntington disease.

We analyzed the data on age at onset and CAG size of 319 patients clinically diagnosed with Huntington disease (HD) and 86 presymptomatic subjects recorded by four Italian Centers over the last 14 years. To overcome the problem of different CAG numbers found in each subject, also in the same family, the data were analyzed in terms of deviations from the average exponential relationship between onset and CAG number. The subject's year of birth was also considered to quantify possible sampling biases. Observations between relatives were compared with those of the whole group. The deviations were equal, on average, in subjects who inherited their HD gene from their fathers or mothers. Overall, our data argue in favor of a greater similarity across the same generation than across successive generations. In particular, an excess of parents with later than expected age of onset was observed, paralleled by a CAG-independent anticipation of onset in parent-child transmissions. These results can be interpreted in terms of a shared environment determining similar departures from the average CAG-onset relationship but also of a systematic effect that differentiates the two generations here examined.

Adolescent↗
PubMed2000

Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy.

Corticobasal degeneration is a sporadic form of tauopathy, involving the cerebral cortex and extrapyramidal motor system. A series of affected subjects was genotyped for a set of genetic markers along the tau protein gene. A specific haplotype is significantly overrepresented in patients versus controls. This haplotype is the same already reported in association with progressive supranuclear palsy. These data show that corticobasal degeneration and progressive supranuclear palsy, in addition to several clinical, pathological, and molecular features, may have the same genetic background.

Aged↗
PubMed1999

Exclusion of the ninjurin gene as a candidate for hereditary sensory neuropathies type I and type II.

Ninjurin is a protein that is up-regulated in Schwann cells and neurons after peripheral nerve injury. Its role in promoting nerve regeneration and its expression in sensory neurons of dorsal root ganglia, as well as the chromosomal localization of the ninjurin gene, makes this gene a candidate for hereditary sensory neuropathies (HSN). In the present report, the human ninjurin gene was analyzed in 17 unrelated patients with HSN type I, two patients with HSN type II, and 10 normal controls, by single strand conformation polymorphism and by direct sequencing. All three exons and splice junctions of the gene were investigated and no mutations were found in our sample of patients. Our results rule out a mutation in the translated region of the ninjurin gene as a cause of HSN type I and type II.

Cell Adhesion Molecules, Neuronal↗
PubMed1999

A novel mutation (D305V) in the early growth response 2 gene is associated with severe Charcot-Marie-Tooth type 1 disease.

Hereditary motor and sensory neuropathies (HMSN) comprises a wide clinical spectrum of related disorders with defects in peripheral nerve myelination. Charcot-Marie-Tooth type 1 (CMT1) is the most common form and is usually a mild disease with onset in the first or second decade; however there is a interfamilial and intrafamilial clinical variation, ranging from asymptomatic expression to severe muscular weakness and atrophy. Recently point mutations in the early growth response 2 gene (EGR2/Krox-20) have been associated with hereditary myelinopathies. We investigated for mutations at the EGR2 gene a patient with severe CMT1 phenotype. Direct sequencing of EGR2 gene showed a heterozygous A T transversion at nucleotide 1064 that predicts an Asp305Val substitution within the first zinc-finger domain. The finding of a novel EGR2 mutation associated with a different phenotype confirms that peripheral neuropathies represent a continuum spectrum of related disorders due to an underlying defect in myelination.

Amino Acid Substitution↗
PubMed1999

Congenital hypomyelination due to myelin protein zero Q215X mutation.

Congenital hypomyelination (CH) is a hereditary demyelinating peripheral neuropathy characterized by early infancy onset, distal muscle weakness, hypotonia, areflexia, and severe slowing of nerve conduction velocities. In the present report, the clinical, morphological, and immunohistochemical features of a CH case and the identification of a mutation in the gene (MPZ) for protein zero (P0) associated with this phenotype are described. This "de novo" mutation in a patient presenting with clinical features quite distinct from those of the more frequent Charcot-Marie-Tooth type 1B disease (CMT1B) or Dejerine-Sottas syndrome (DSS) confirms that CH is allelic with other disorders characterized by a less severe phenotype and a different clinical and neuropathological profile.

Demyelinating Diseases↗
PubMed1999

Isolation and characterization of a novel transcript embedded within HIRA, a gene deleted in DiGeorge syndrome.

We have isolated a few cDNAs from different human tissues, transcribed from the first intron of HIRA, a gene deleted in the DiGeorge syndrome. These cDNAs are produced by an intronic gene (22k48) which is transcribed by the HIRA opposite strand and is itself arranged in exons and subjected to alternative splicing. The longest continuum cDNA sequence we obtained is 3.6 kb long and contains 3 different exons and 2 introns. 22k48 cDNA is composed of several tandemly arranged repeated elements (Alu, LINEs, CAn) surrounding a unique sequence. In situ hybridization showed the presence of 22k48 RNA in the cytoplasm of CNS and PNS neurons. 22k48 RNA is able to bind cytoplasmic proteins in the range of 45 to 60 kDa. 22k48 is a new member of the small group of genes that are transcribed but not translated, and its haploinsufficiency could contribute to the pathogenesis of the DiGeorge syndrome.

Adult↗
PubMed1998

Predictive testing for Huntington's disease: ten years' experience in two Italian centres.

Pre-symptomatic testing for Huntington's disease (HD) has been available as a clinical service in the medical centres of Rome and Genoa since December 1987, initially by DNA-linkage and since mid-1993 by direct mutation analysis. A multidisciplinary approach and a protocol which follows the Ethical Issue Policy Statement on Huntington's Disease Molecular Genetics Predictive Test has been used. In the period under study, 332 subjects requested the test, 288 were enrolled in the protocol and nearly half of these completed it. One hundred and forty-eight people withdrew from the testing procedure for various reasons but most frequently due to a more realistic evaluation of all possible consequences of test results, induced by psychological counselling. Therefore, 140 people completed the test. The overall gene-carrier/non-carrier ratio was 0.46:1. None of the identified gene carriers had catastrophic reactions such as suicide, suicide attempts or major psychiatric disorders. All appear to have had a similar pattern of reactions to an adverse result and none expressed regret for undergoing the test. In conclusion, presymptomatic testing for HD can be considered a safe procedure without adverse consequences when framed in an integrated protocol at qualified genetic centres.

Adaptation, Psychological↗
PubMed1997

mRNA distribution in adult human brain of GRIN2B, a N-methyl-D-aspartate (NMDA) receptor subunit.

The expression of the N-methyl-D-aspartate (NMDA) receptor subunit NR2B/epsilon2 (GRIN2B) in the human adult brain was assayed by in situ hybridisation, by using a specific cRNA probe. The full length GRIN2B cDNA was cloned and sequenced. It showed a 90% nucleotide conservation when compared to the rodent homologue. GRIN2B gene is expressed at high levels in the fronto-parieto-temporal cortex and hippocampus pyramidal cells and, at a lower extent, in the basal ganglia (amygdala and striatum). The cerebellar granule cells does not show any mRNA expression. The non-ubiquitous anatomical distribution of the GRIN2B mRNA in the central nervous system suggests that the gene could be involved in specific functions pertaining to the expressing cell groups.

Adult↗
PubMed1997

Correlation between PMP-22 messenger RNA expression and phenotype in hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a deletion in chromosome 17p11.2, which includes the gene for the peripheral myelin protein 22 (PMP-22). A "gene dosage" effect is probably the mechanism underlying HNPP, but the amount of PMP-22 mRNA in sural nerves of HNPP patients is highly variable and the role of PMP-22 underexpression in impairing myelination has yet to be clarified. We have studied 6 genetically proven HNPP patients, to evaluate the relationship between PMP-22 mRNA levels, and clinical, neurophysiological, and neuropathological findings. Underexpression of PMP-22 mRNA correlates with disease severity and with mean axon diameter and g ratio, but not with myelin thickness, number of "tomacula," or nerve conduction parameters. Our findings further confirm that underexpression of PMP-22 is the main pathogenetic mechanism underlying the severity of clinical symptoms and signs in HNPP. Smaller axons in sural nerves of HNPP patients with lower PMP-22 levels suggests that underexpression of PMP-22 may also affect axon development.

Charcot-Marie-Tooth Disease↗
PubMed1997

Underexpression of messenger RNA for peripheral myelin protein 22 in hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a deletion in chromosome 17p11.2, including the gene for the peripheral myelin protein 22 (PMP-22). Because of the proposal that a decreased dosage of the PMP-22 gene was the cause of HNPP, we evaluated sural nerves from eight patients with the 17p11.2 deletion and from five normal controls. The relative amount of PMP-22 mRNA was significantly lower in HNPP patients compared with normal controls (p < 0.02) using a semiquantitative reverse transcriptase-polymerase chain reaction. There was no significant decrease of Pzero mRNA. Sural nerves from HNPP patients showed normal immunostaining with monoclonal antibodies against PMP-22, Pzero, and myelin basic protein, and only rare myelinated fibers, classified as "tomacula," showed a patchy staining of the compact myelin with monoclonal antibody against PMP-22. The significant underexpression of PMP-22 mRNA in HNPP patients compared with normal controls demonstrates that a decreased dosage of the PMP-22 gene is the most likely pathogenetic mechanism in HNPP.

Base Sequence↗