Five novel locations of Neocentromeres in human: 18q22.1, Xq27.1∼27.2, Acro p13, Acro p12, and heterochromatin of unknown origin.

Since the first report in 1993, an ectopic centromere, i.e. neocentromere formation, has been reported in more than 100 small supernumerary marker chromosomes (sSMC), in 7 instances of centromere repositioning, and in about a dozen cases with more complex chromosomal rearrangements.

Impaired fear extinction in mice lacking protease nexin-1.

The serine protease inhibitor protease-nexin-1 (PN-1) has been shown to modulate N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic currents and NMDAR-dependent long-term potentiation of synaptic transmission. Here, we analysed the role of PN-1 in the acquisition and extinction of classical auditory fear conditioning, two distinct forms of learning that both depend on NMDAR activity in the amygdala. Immunostaining revealed that PN-1 is expressed throughout the amygdala, primarily in gamma-aminobutyric acid containing neurons of the central amygdala and intercalated cell masses (ITCs) and in glia.

Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome.

Background: Roberts syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2, which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be truncating mutations. Genotype-phenotype analysis has been hampered by limited numbers of patients with clinical information available.

10p11.2 to 10q11.2 is a yet unreported region leading to unbalanced chromosomal abnormalities without phenotypic consequences.

Directly transmitted unbalanced chromosomal abnormalities (UBCA) or euchromatic variants (EV) were recently reported for >50 euchromatic regions of almost all human autosomes. UBCA and EV are comprised of a few megabases of DNA, and carriers are in many cases clinically healthy. Here we report on partial trisomies of chromosome 10 within the pericentromeric region which were detected by standard G banding.

The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity.

Roberts syndrome/SC phocomelia (RBS) is an autosomal recessive disorder with growth retardation, craniofacial abnormalities and limb reduction. Cellular alterations in RBS include lack of cohesion at the heterochromatic regions around centromeres and the long arm of the Y chromosome, reduced growth capacity, and hypersensitivity to DNA damaging agents. RBS is caused by mutations in ESCO2, which encodes a protein belonging to the highly conserved Eco1/Ctf7 family of acetyltransferases that is involved in regulating sister chromatid cohesion.

Novel mutations in exon 6 of the GFAP gene affect a highly conserved if motif in the rod domain 2B and are associated with early onset infantile Alexander disease.

Alexander disease is a rare disorder of cerebral white matter due to a dysfunction of astrocytes. The most common infantile form presents as a megalencephalic leukodystrophy. Mutations of the GFAP gene, encoding Glial Fibrillary Acidic Protein, have been recognized as the cause of Alexander disease.

Severe Guillain-Barré syndrome associated with chromosome 17p11.2-12 duplication.

We report a patient with Guillain-Barré syndrome (GBS), characterized by severe tetraparesis, bulbar syndrome, and ophthalmoparesis. The nadir was reached within 1 day, followed by respiratory insufficiency requiring mechanical ventilation. Molecular analysis revealed a duplication at chromosome 17p11.

Mice deficient for RNA-binding protein brunol1 show reduction of spermatogenesis but are fertile.

RNA-binding proteins are involved in post-transcriptional processes like mRNA stabilization, alternative splicing, and transport. Brunol1 is a novel mouse gene related to elav/Bruno family of genes encoding for RNA-binding proteins. We report here the expression and functional analysis of murine Brunol1.

Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2).

Background: Charcot-Marie-Tooth neuropathies are a group of genetically heterogeneous diseases of the peripheral nervous system. Mutations in the MFN2 gene have been reported as the primary cause of Charcot-Marie-Tooth disease type 2A.

Methods: Patients with the clinical diagnosis of Charcot-Marie-Tooth type 2 were screened using single strand conformation polymorphism (SSCP).

Electrophoresis of DNA in human genetic diagnostics - state-of-the-art, alternatives and future prospects.

Electrophoretic separation of nucleic acids according to their molecular weights has dominated the methods' spectrum in molecular genetics for nearly half a century. We review the current methodological basis and evaluate its impact with special reference to new developments in the microarray technology. Although electrophoresis may be made redundant for many applications in DNA diagnostics within a few years, a number of electrophoretic vestiges will remain irreplaceable in the foreseeable future.

Thrombin in ischemic neuronal death.

Thrombin plays a role in cerebral ischemia as rats subjected to focal cerebral ischemia were protected by the intracerebral injection of hirudin, a selective thrombin inhibitor. To separate the roles of thrombin in cell death and in coagulation, we have used an in vitro approach to test the effect of hirudin and of protease nexin-1 (PN-1), a cerebral thrombin inhibitor, on neuronal ischemia. Rat organotypic hippocampal slice cultures were subjected to oxygen (5%) and glucose (1 mmol/L) deprivation (OGD) during 30 min.

Novel case of dup(3q) syndrome due to a de novo interstitial duplication 3q24-q26.31 with minimal overlap to the dup(3q) critical region.

Dup(3q) syndrome is characterized by typical facial features, mental and growth retardation, often with congenital heart defects. The syndrome has attracted special attention because of the clinical overlap with Cornelia de Lange syndrome (CDLS). Patients with dup(3q) syndrome are trisomic for segments of the long arm of chromosome 3, most often within the region 3q21 to 3qter.

Regulation of brain proteolytic activity is necessary for the in vivo function of NMDA receptors.

Serine proteases are considered to be involved in plasticity-related events in the nervous system, but their in vivo targets and the importance of their control by endogenous inhibitors are still not clarified. Here, we demonstrate the crucial role of a potent serine protease inhibitor, protease nexin-1 (PN-1), in the regulation of activity-dependent brain proteolytic activity and the functioning of sensory pathways. Neuronal activity regulates the expression of PN-1, which in turn controls brain proteolytic activity.

First non-mosaic case of isopseudodicentric chromosome 18 (psu idic(18)(pter --> q22.1::q22.1 --> pter) is associated with multiple congenital anomalies reminiscent of trisomy 18 and 18q- syndrome.

Isopseudodicentric chromosome 18 is very rare and results in a combination of partial trisomy and partial monosomy of chromosome 18. We report here a hypotrophic newborn with a lateral cleft lip and palate and multiple craniofacial dysmorphisms, a combined heart defect, unilateral hypoplasia of the kidney, bilateral aplasia of thumbs, and generalized contractures. Cytogenetic analysis revealed an isopseudodicentric chromosome 18 with breakpoint in 18q (46,XX,psu idic(18)(pter --> q22.

Prothrombin overexpressed in post-natal neurones requires blood factors for activation in the mouse brain.

Thrombin is thought to mediate, through protease-activated receptors, both protective as well as cytotoxic effects. As thrombin receptors are expressed in the CNS, an important question arises as to whether the intact nervous system is able to generate thrombin by activation of its precursor prothrombin, derived endogenously or only upon extravasation following brain injury. To address this question, transgenic mice that express C-terminally haemagglutinin tagged human prothrombin in post-mitotic neurones were generated.

A novel GFAP mutation and disseminated white matter lesions: adult Alexander disease?

The recent discovery of heterozygous de novo mutations in the glial fibrillary acidic protein (GFAP) gene as the cause of infantile and juvenile Alexander disease has shed new light on the long-standing debate whether the adult subtype has the same etiology as infantile and juvenile Alexander disease. A 40-year-old man presented with subacute left hemiplegia and ataxia. Cranial MRI revealed disseminated patchy white matter changes involving the corpus callosum, basal ganglia and brainstem.

Cerebral proton magnetic resonance spectroscopy in infantile Alexander disease.

Alexander disease (AD) is a rare genetic disorder of the central nervous system due to a dysfunction of astrocytes. The most common infantile form presents as a progressive leukodystrophy with macrocephalus. Recently, heterozygous de novo mutations in the gene encoding glial fibrillary acidic protein (GFAP) have been demonstrated to be associated with AD.

A novel family-specific translocation t(2;20)(p24.1;q13.1) associated with recurrent abortions: molecular characterization and segregation analysis in male meiosis.

In the present study, we present a novel reciprocal translocation t(2;20)(p24.1;q13.1) and its segregation in a three generation family.

Evaluation of Cx26/GJB2 in German hearing impaired persons: mutation spectrum and detection of disequilibrium between M34T (c.101T>C) and -493del10.

Mutations in the connexin 26 gene (GJB2) are responsible for the major part of nonsyndromic autosomal recessive or apparently sporadic prelingual deafness in Caucasians (DFNB1). We screened 228 German hearing-impaired persons for mutations in the GJB2 gene by sequence analysis. Homozygous or compound heterozygous GJB2 mutations were detected in 38/228 (16.

Identification and characterization of murine Brunol4, a new member of the elav/bruno family.

RNA-binding proteins are involved in post-transcriptional processes like mRNA stabilization, post-transcriptional modification, and transport and have been suggested to play an important role in developmental gene regulation. We report here the cloning and characterization of Brunol4, a novel mouse cDNA closely related to the elav-type family of genes encoding for RNA-binding proteins and a subfamily recently named after the bruno gene of Drosophila. Murine Brunol4 is localized near the centromere of chromosome 18.

Infantile Alexander disease: a GFAP mutation in monozygotic twins and novel mutations in two other patients.

Alexander disease (AD) is a rare disorder of cerebral white matter due to a dysfunction of astrocytes. The most common infantile form presents as a megalencephalic leukodystrophy. Recently, heterozygous de novo mutations in the glial fibrillary acidic protein gene (GFAP) have been demonstrated to be associated with AD.

Expression of Drosophila omb-related T-box genes in the developing human and mouse neural retina.

Purpose: To examine the role of Drosophila optomotor blind (omb)-related T-box genes in development of human and mouse retina.

Methods: Mouse Tbx2, Tbx3, and Tbx5 and human TBX2 cDNAs were isolated from retinal cDNA libraries by hybridization to the Drosophila omb gene. Gene expression patterns in developing retina were analyzed by in situ hybridization.

Progressive neuronal and motor dysfunction in mice overexpressing the serine protease inhibitor protease nexin-1 in postmitotic neurons.

Perturbation of the homeostasis between proteases and their inhibitors has been associated with lesion-induced or degenerative neuronal changes. Protease nexin-1 (PN-1), a secreted serine protease inhibitor, is constitutively expressed in distinct neuronal cell populations of the adult CNS. In an earlier study we showed that transgenic mice with ectopic or increased expression of PN-1 in postnatal neurons have altered synaptic transmission.