Microarray-based copy number analysis of neurofibromatosis type-1 (NF1)-associated malignant peripheral nerve sheath tumors reveals a role for Rho-GTPase pathway genes in NF1 tumorigenesis.

Neurofibromatosis type-1 (NF1) is associated with the growth of benign and malignant tumors. Approximately 15% of NF1 patients develop malignant peripheral nerve sheath tumors (MPNSTs), underlining the need to identify specific diagnostic/prognostic biomarkers associated with MPNST development. The Affymetrix Genome-Wide Human single-nucleotide polymorphism (SNP) Array 6.

Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas.

Neurofibromatosis type-1 (NF1), caused by heterozygous inactivation of the NF1 tumour suppressor gene, is associated with the development of benign and malignant peripheral nerve sheath tumours (MPNSTs). Although numerous germline NF1 mutations have been identified, relatively few somatic NF1 mutations have been described in neurofibromas. Here we have screened 109 cutaneous neurofibromas, excised from 46 unrelated NF1 patients, for somatic NF1 mutations.

Confirmation that the specific SSLP microsatellite allele 4qA161 segregates with fascioscapulohumeral muscular dystrophy (FSHD) in a cohort of multiplex and simplex FSHD families.

The molecular defect in fascioscapulohumeral muscular dystrophy (FSHD) has proved difficult to explain. Although contraction within a polymorphic tandem repeat located at 4q35.2 is unequivocally associated with disease expression, the specific biological mechanism involved in the phenotype has yet to be resolved.

NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype.

In 5-10% of patients, neurofibromatosis type 1 (NF1) results from microdeletions that encompass the entire NF1 gene and a variable number of flanking genes. Two recurrent microdeletion types are found in most cases, with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP-c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.

Molecular evolution of a neurofibroma to malignant peripheral nerve sheath tumor (MPNST) in an NF1 patient: correlation between histopathological, clinical and molecular findings.

Objective: Neurofibromatosis type 1 (NF1) patients have a 13% risk of developing a malignant peripheral nerve sheath tumor (MPNST). Many MPNSTs are histopathologically complex, with regions exhibiting features of the original benign plexiform neurofibroma (PNF), of an atypical PNF, or of MPNST showing varying degrees of de-differentiation. This study analyzed the genetic alterations associated with this pathological heterogeneity in order to identify the genetic processes involved in transformation from a benign to an aggressive malignant tumor.

SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the neurofibromatosis type 1 phenotype.

Objective: Mutations of the SPRED1 gene, one of a family of Sprouty (Spry)/Spred proteins known to "downregulate" mitogen activated protein kinase (MAPK) signalling, have been identified in patients with a mild neurofibromatosis type 1 (NF1) phenotype with pigmentary changes but no neurofibromas (Legius syndrome).To ascertain the frequency of SPRED1 mutations as a cause of this phenotype and to investigate whether other SPRED/SPRY genes may be causal, a panel of unrelated mild NF1 patients were screened for mutations of the SPRED1-3 and the SPRY1-4 genes.

Methods: 85 patients with a mild NF1 phenotype were screened for SPRED1 mutations.

The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas.

Neurofibromatosis type 1 (NF1) is a common inherited complex multi-system disorder associated with the growth of various benign and malignant tumors. About 40% of NF1 patients develop spinal tumors, of whom some have familial spinal neurofibromatosis (FSNF), a variant form of NF1 in which patients present with multiple bilateral spinal tumors but have few other clinical features of the disease. We have studied 22 spinal neurofibromas derived from 14 unrelated NF1 patients.

Further evidence for the association of MMP9 with nephropathy in type 2 diabetes and application of DNA pooling technology to candidate gene screening.

Background: Diabetic nephropathy is characterised by extracellular matrix (ECM) expansion, a key modulator of which is TGF-b1. Glucose-stimulated transcriptional activation of the TGF-b1 gene is an important component of the pathogenesis of nephropathy, following which latent TGF-b1 protein is synthesised. Matrix metalloproteinase 9 (MMP9) remodels the ECM and has been implicated in TGF-b1 activation.

Germline and somatic NF1 gene mutations in plexiform neurofibromas.

Neurofibromatosis type 1 (NF1), a common autosomal dominant neurogenetic disorder affecting 1 in 4000 individuals worldwide, results from functional inactivation of the 17q11.2-located NF1 gene. Plexiform neurofibroma (PNF) is a congenital benign tumour present in 30-50% of NF1 patients, which in about 10-15% of cases, can develop into a malignant peripheral nerve sheath tumour (MPNST).

Congenital disseminated neurofibromatosis type 1: a clinical and molecular case report.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition with a birth incidence of 1/3,500. Around 50% of cases are due to new mutations. The NF1 gene maps to 17q11.

High-resolution DNA copy number profiling of malignant peripheral nerve sheath tumors using targeted microarray-based comparative genomic hybridization.

Purpose: Neurofibromatosis type 1 (NF1) is an autosomal dominant condition that predisposes to benign and malignant tumors. The lifetime risk of a malignant peripheral nerve sheath tumor (MPNST) in NF1 is approximately 10%. These tumors have a poor survival rate and their molecular basis remains unclear.

Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use.

Background: Genetic variations might modify associations between schizophrenia and cannabis or tobacco use.

Aims: To examine whether variants within the cannabinoid receptor (CNR1) and alpha(7) nicotinic receptor (CHRNA7) genes are associated with schizophrenia, and whether these effects vary according to cannabis or tobacco use. We also examined a putative interaction between cannabis and Val(158)Met within the catechol-O-methyltransferase gene (COMT).

Germline and somatic NF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumors (MPNSTs).

About 10% of neurofibromatosis type 1 (NF1) patients develop malignant peripheral nerve sheath tumors (MPNSTs) and represent considerable patient morbidity and mortality. Elucidation of the genetic mechanisms by which inherited and acquired NF1 disease gene variants lead to MPNST development is important. A study was undertaken to identify the constitutional and somatic NF1 mutations in 34 MPNSTs from 27 NF1 patients.

Somatic alterations of the NF1 gene in an NF1 individual with multiple benign tumours (internal and external) and malignant tumour types.

Neurofibromatosis type 1 is a common familial cancer syndrome, affecting about 1 in every 4,000 individuals worldwide. We have carried out NF1 gene mutation analysis on DNA isolated from 25 tumours (dermal and plexiform neurofibromas, malignant peripheral nerve sheath tumour, MPNST), obtained at post-mortem from an NF1 patient. Macro and micro sequence alterations of the NF1 gene were studied by dHPLC, microsatellite, RFLP markers and multiplex ligation probe amplification (MLPA).

A novel mutation in the NF1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma.

We present the clinical and ophthalmological findings, genetic analysis, and therapy of two siblings with NF1 and bilateral OPG. In genetic analysis, a heteroduplex profile was detected in exon 4b of the NF1 gene for the affected patients and mother. Sequencing of the DNA samples identified a C > T nucleotide change in exon 4b (c484CAG > TAG).

A large patient study confirming that facioscapulohumeral muscular dystrophy (FSHD) disease expression is almost exclusively associated with an FSHD locus located on a 4qA-defined 4qter subtelomere.

Facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant disorder, represents the third most common human muscular dystrophy. The FSHD disease locus, at chromosome 4q35, is associated with large contractions of the polymorphic repeat sequence array D4Z4. In addition to FSHD disease association with large D4Z4 deletions, a biased interaction with a specific 4qter subtelomeric sequence has been described in patients.

The heterogeneous nature of germline mutations in NF1 patients with malignant peripheral serve sheath tumours (MPNSTs).

Malignant peripheral nerve sheath tumours (MPNSTs) are a major cause of mortality in patients with neurofibromatosis 1 (NF1). We have analysed lymphocyte DNA samples from 30 NF1 patients with MPNSTs to determine their underlying constitutional NF1 gene mutations. Mutations were detected in 27/30 (90%) of these patients.

Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia.

There is now strong evidence that Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. NRG1 mediates some of its effects through the tyrosine kinase receptor erbB4, and analysis of gene knock-out animals suggests that the functional interaction of NRG1 and erbB4 mediates behaviors that may model some aspects of the schizophrenia phenotype in mice. Given these findings, we have sought evidence for association between schizophrenia and erbB4.

Identification in 2 independent samples of a novel schizophrenia risk haplotype of the dystrobrevin binding protein gene (DTNBP1).

Context: Recent research suggests that variation in the gene encoding dystrobrevin binding protein (DTNBP1) confers susceptibility to schizophrenia. Thus far, no specific risk haplotype has been identified in more than 1 study.

Objectives: To confirm DTNBP1 as a schizophrenia susceptibility gene, to identify and replicate specific risk and protective haplotypes, and to explore relationships between DTNBP1 and the phenotype.

Support for RGS4 as a susceptibility gene for schizophrenia.

Background: The gene encoding the regulator of G-protein signaling 4 has recently been associated with susceptibility to schizophrenia. This finding is particularly interesting, because it was replicated within the same study and also because there are functional, positional, and expression data to support the regulator of G-protein signaling 4 as a schizophrenia candidate gene. Although the original report was highly suggestive, a limitation was that the study was conducted on rather small samples.

Screening the human protocadherin 8 (PCDH8) gene in schizophrenia.

Abnormalities in synaptic connectivity and plasticity have been implicated in the pathophysiology of schizophrenia. Molecules involved in the development and maintenance of neural circuitry include the recently cloned protocadherins. Human protocadherin 8 (PCDH8) is homologous to 'arcadlin', a molecule shown to play a role in hippocampal synaptic function in the rat.