12 research outputs found
Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous disorder. All mendelian patterns of inheritance have been described. We identified a homozygous p.A335V mutation in the MED25 gene in an extended Costa Rican family with autosomal recessively inherited Charcot-Marie-Tooth neuropathy linked to the CMT2B2 locus in chromosome 19q13.3. MED25, also known as ARC92 and ACID1, is a subunit of the human activator-recruited cofactor (ARC), a family of large transcriptional coactivator complexes related to the yeast Mediator. MED25 was identified by virtue of functional association with the activator domains of multiple cellular and viral transcriptional activators. Its exact physiological function in transcriptional regulation remains obscure. The CMT2B2-associated missense amino acid substitution p.A335V is located in a proline-rich region with high affinity for SH3 domains of the Abelson type. The mutation causes a decrease in binding specificity leading to the recognition of a broader range of SH3 domain proteins. Furthermore, Med25 is coordinately expressed with Pmp22 gene dosage and expression in transgenic mice and rats. These results suggest a potential role of this protein in the molecular etiology of CMT2B2 and suggest a potential, more general role of MED25 in gene dosage sensitive peripheral neuropathy pathogenesis
A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype
La mutaciĂłn p.thr124Met en la proteĂna mielina cero (MPZ) causa la enfermedad de Charcot-Marie-Tooth tipo 2J, una neuropatĂa perifĂ©rica con sĂntomas adicionales como alteraciones pupilares y sordera. Se ha observado en varias familias alrededor del mundo, originarias de Alemania, BĂ©lgica, JapĂłn, Italia y NorteamĂ©rica, entre otras. AquĂ reportamos a pacientes centroamericanos provenientes de Costa Rica que acarrean esta mutaciĂłn. Se realizaron análisis clĂnico, electrofisiolĂłgico y molecular de pacientes y controles, incluyendo secuenciaciĂłn del gen y de marcadores ligados a Ă©ste. Estos pacientes comparten casi por completo el haplotipo con dos pacientes belgas no emparentados. Como resultado del análisis de los haplotipos, basado en diez marcadores (siete SNPs, dos microsatĂ©lites y un elemento poli-A intrĂłnico), se sugiere que se ha dado un efecto fundador en la migraciĂłn de este alelo.The p.Thr124Met mutation in the myelin protein zero (MPZ) causes the Charcot-Marie-Tooth disease type 2J, a peripheral neuropathy with additional symptoms as pupillary alterations and deafness. It was observed in several families around the world originating e. g. from Germany, Belgium, Japan, Italy and North America. Here we report Central American patients originating from a family in Costa Rica carrying this mutation. Clinical, electrophysiological and molecular analysis of patients and controls were performed, including gene and linked markers´ sequencing. Carriers share almost the entire haplotype with two non related Belgian CMT patients. As a result of the haplotype analysis, based on ten markers (seven SNPs, two microsatellites and an intronic polyA stretch), the founder effect hypothesis for this allele migration is suggestive.UCR::VicerrectorĂa de InvestigaciĂłn::Unidades de InvestigaciĂłn::Ciencias de la Salud::Centro de InvestigaciĂłn en Neurociencias (CIN
Late onset autosomal dominant Charcot– Marie–Tooth 2 neuropathy in a Costa Rican family
Objective: To describe the clinical, electrophysiologic and morphologic features of a Costa
Rican family with an autosomal dominant inherited Charcot–Marie–Tooth (CMT) neuropathy.
Methods: The field study took place in Costa Rica, Central America. Seven patients underwent
neurological examinations and standard electrodiagnostic tests, and a sural nerve biopsy was taken
from one patient. Fifteen family members were screened for gene defects associated with CMT disease.
Results: Characteristic features of this family were a late age of onset (35–56 years), positive
sensory symptoms and muscle cramps. Based on electrodiagnostic and morphologic data, the
patients were classified as having a CMT2 neuropathy. The CMT1A duplication/HNPP deletion
and point mutations in genes PMP22, MPZ, Cx32 and EGR2 implicated in the most common
types of CMT disease were excluded. Subsequently, almost all known CMT loci were excluded
by linkage analysis.
Discussion: Features of this family were a late age of onset and positive sensory symptoms. This
new autosomal dominant CMT neuropathy is associated with an unknown gene defect. [Neurol
Res 2009; 31: 283–288]Objetivo: Describir las caracterĂsticas clĂnicas, electrofisiolĂłgicas y morfolĂłgicas de una familia costarricense con una neuropatĂa de Charcot-Marie-Tooth (CMT) hereditaria autosĂłmica dominante. MĂ©todos: El estudio de campo se llevĂł a cabo en Costa Rica, CentroamĂ©rica. Siete pacientes se sometieron a exámenes neurolĂłgicos y pruebas de electrodiagnĂłstico estándar, ya un paciente se le tomĂł una biopsia del nervio sural. Quince miembros de la familia fueron evaluados por defectos genĂ©ticos asociados con la enfermedad de CMT. Resultados: Los rasgos caracterĂsticos de esta familia fueron una edad de inicio tardĂa (35-56 años), sĂntomas sensoriales positivos y calambres musculares. Sobre la base de los datos morfolĂłgicos y de electrodiagnĂłstico, los pacientes se clasificaron con una neuropatĂa CMT2. Se excluyeron la duplicaciĂłn de CMT1A/deleciĂłn HNPP y las mutaciones puntuales en los genes PMP22, MPZ, Cx32 y EGR2 implicados en los tipos más comunes de enfermedad de CMT. Posteriormente, casi todos los loci CMT conocidos fueron excluidos por análisis de ligamiento. DiscusiĂłn: Las caracterĂsticas de esta familia fueron una edad de inicio tardĂa y sĂntomas sensoriales positivos. Esta nueva neuropatĂa de CMT autosĂłmica dominante está asociada con un defecto genĂ©tico desconocido. [NeurolRes 2009; 31: 283–288]Universidad Nacional, Costa Rica.Escuela de Ciencias BiolĂłgica
Clinical and electrophysiological characteristics of autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2B) that maps to chromosome 19q13.3
ArtĂculo cientĂfico -- Universidad de Costa Rica. Instituto de Investigaciones en Salud, 2004. Este documento es privado debido a limitaciones de derechos de autor.Cbarcot-Marie-Tooth disease (CMT) comprises a heterogeneous group of hereditary motor and sensory peripheral neuropathies. The
autosomal recessive axonal form of CMT (ARCMT2) is ram. Eight patients of a large consanguineous family of Spanish ancestry in Costa
Rica were diagnosed with ARCMT2B; previous genetic studies of this family revealed linkage to chromosome 19q13.3. The clinical and
electrophysiological features of these patieets are reported. All patients presented with a symmetric motor and sensory neuropathy. which
was more pronounced in the lower limbs. Ftuther, distal muscle wasting and impaired deep tendon reflexes were found. Age at onset was
between 26 and 42 years, and the disease duration ranged from 2 to 19 yours. Electrophysiological medics revealed a primary tumuli
degenerative process. The clinical characteristics of this family differed in several aspects from previously reported families with ARCMT2.Universidad de Costa Rica, Instituto de Investigaciones en SaludUCR::VicerrectorĂa de InvestigaciĂłn::Unidades de InvestigaciĂłn::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA
Charcot-Marie-Tooth disease: a novel Tyr145Ser mutation in the myelin protein zero (MPZ, P0) gene causes different phenotypes in homozygous and heterozygous carriers within one family
artĂculo -- Universidad de Costa Rica. Instituto de Investigaciones en Salud, 2003Abstract. Charcot-Marie-Tooth disease type IB (CMT 1B) is caused by mutations in the gene
coding for peripheral myelin protein zero (MPZ, P0) that plays a fundamental role in adhesion
and compaction of peripheral myelin. Here we report a Costa Rican family with a hereditary
peripheral neuropathy due to a novel Tyr145Ser MPZ mutation. Four family members were heterozygously affected; two siblings of two heterozygous carriers were homozygous for this
mutation. On neurological examination the heterozygous parents and their homozygous children
both showed distal sensory deficits. The mother and the siblings displayed impaired deep tendon
reflexes and mild sensory ataxia. The homozygous individuals were more severely affected with
an earlier age of onset, distal motor weakness, and pupillary abnormalities. Electrophysiological
studies revealed both signs of demyelination and axonal nerve degeneration. The sural nerve
biopsy of one sibling showed thinly myelinated nerve fibers, onion bulb formation, and clusters
of regenerating fibers. On electron microscopy axonal degeneration and decompaction of inner
myelin layers were found. This Costa Rican family shows phenotypic variability depending on
the homozygous or heterozygous state of the Tyr145Ser mutation carriers.info:eu-repo/grantAgreement/Universidad de Costa Rica/Instituto de Investigaciones PsicolĂłgicas ////UCR::VicerrectorĂa de InvestigaciĂłn::Unidades de InvestigaciĂłn::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA
The nucleotide sequence of Saccharomyces cerevisiae chromosome XII.
The yeast Saccharomyces cerevisiae is the pre-eminent organism for the study of basic functions of eukaryotic cells. All of the genes of this simple eukaryotic cell have recently been revealed by an international collaborative effort to determine the complete DNA sequence of its nuclear genome. Here we describe some of the features of chromosome XII.Journal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.SCOPUS: ar.jinfo:eu-repo/semantics/publishe
A Second Locus for an Axonal Form of Autosomal Recessive Charcot-Marie-Tooth Disease Maps to Chromosome 19q13.3
Autosomal recessive Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of disorders affecting the peripheral nervous system. The axonal form of the disease is designated as ”CMT type 2” (CMT2), and one locus (1q21.2-q21.3) has been reported for the autosomal recessive form. Here we report the results of a genomewide search in an inbred Costa Rican family (CR-1) affected with autosomal recessive CMT2. By analyzing three branches of the family we detected linkage to the 19q13.3 region, and subsequent homozygosity mapping defined shared haplotypes between markers D19S902 and D19S907 in a 5.5-cM range. A maximum two-point LOD score of 9.08 was obtained for marker D19S867, at a recombination fraction of .00, which strongly supports linkage to this locus. The epithelial membrane protein 3 gene, encoding a PMP22 homologous protein and located on 19q13.3, was ruled out as being responsible for this form of CMT. The age at onset of chronic symmetric sensory-motor polyneuropathy was 28–42 years (mean 33.8 years); the electrophysiological data clearly reflect an axonal degenerative process. The phenotype and locus are different from those of demyelinating CMT4F, recently mapped to 19q13.1-13.3; hence, the disease affecting the Costa Rican family constitutes an axonal, autosomal recessive CMT subtype (ARCMT2B)
Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily
Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-κB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-κBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-κB and NF-κB–dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-κB activation was blunted in RAGE-null (RAGE(–/–)) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE(–/–) mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE–NF-κB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches