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 mutación p.thr124Met en la proteína mielina cero (MPZ) causa la enfermedad de Charcot-Marie-Tooth tipo 2J, una neuropatía periférica con síntomas adicionales como alteraciones pupilares y sordera. Se ha observado en varias familias alrededor del mundo, originarias de Alemania, Bélgica, Japón, Italia y Norteamérica, entre otras. Aquí reportamos a pacientes centroamericanos provenientes de Costa Rica que acarrean esta mutación. Se realizaron análisis clínico, electrofisiológico y molecular de pacientes y controles, incluyendo secuenciación del gen y de marcadores ligados a éste. 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 microsatélites y un elemento poli-A intrónico), se sugiere que se ha dado un efecto fundador en la migración 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::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación 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 características clínicas, electrofisiológicas y morfológicas de una familia costarricense con una neuropatía de Charcot-Marie-Tooth (CMT) hereditaria autosómica dominante. Métodos: El estudio de campo se llevó a cabo en Costa Rica, Centroamérica. Siete pacientes se sometieron a exámenes neurológicos y pruebas de electrodiagnóstico estándar, ya un paciente se le tomó una biopsia del nervio sural. Quince miembros de la familia fueron evaluados por defectos genéticos asociados con la enfermedad de CMT. Resultados: Los rasgos característicos de esta familia fueron una edad de inicio tardía (35-56 años), síntomas sensoriales positivos y calambres musculares. Sobre la base de los datos morfológicos y de electrodiagnóstico, los pacientes se clasificaron con una neuropatía CMT2. Se excluyeron la duplicación de CMT1A/deleción 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. Discusión: Las características de esta familia fueron una edad de inicio tardía y síntomas sensoriales positivos. Esta nueva neuropatía de CMT autosómica dominante está asociada con un defecto genético desconocido. [NeurolRes 2009; 31: 283–288]Universidad Nacional, Costa Rica.Escuela de Ciencias Biológica

The polynucleotide kinase 3′-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25

Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of hereditary peripheral neuropathies. We previously reported a CMT locus on chromosome 19q13.3 segregating with the disease in a large Costa Rican family with axonal neuropathy and autosomal recessive pattern of inheritance (CMT2B2). We proposed a homozygous missense variant in the Mediator complex 25 (MED25) gene as causative of the disease.Nevertheless, the fact that no other CMTindividuals withMED25 variants were reported to date led us to reevaluate the original family. Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3′-phosphatase (PNKP) gene. It encodes a DNA repair protein recently associated with recessive ataxia with oculomotor apraxia type 4 (AOA4) and microcephaly, seizures, and developmental delay (MCSZ). Subsequently, five unrelated Costa Rican CMT2 subjects initially identified as being heterozygous for the sameMED25 variant were found to be also compound heterozygote for PNKP. All were heterozygous for the same variant found homozygous in the large family and a second one previously associated with ataxia (p.Thr408del). Detailed clinical reassessment of the initial family and the new individuals revealed in all an adult-onset slowly progressive CMT2 associated with signs of cerebellar dysfunction such as slurred speech and oculomotor involvement, but neither microcephaly, seizures, nor developmental delay. We propose that PKNP variants are the major causative variant for the CMT2 phenotype in these individuals and that the milder clinical manifestation is due to an allelic effect.La enfermedad de Charcot-Marie-Tooth (CMT) representa un grupo heterogéneo de neuropatías periféricas hereditarias. Nosotros anteriormente informaron un locus CMT en el cromosoma 19q13.3 que se segrega con la enfermedad en una gran familia costarricense con neuropatía axonal y patrón de herencia autosómico recesivo (CMT2B2). Propusimos una variante homocigótica sin sentido en el Mediador gen complejo 25 (MED25) como causante de la enfermedad. Sin embargo, el hecho de que ningún otro CMTiindividuos con variantes MED25 reportados hasta la fecha nos llevaron a reevaluar a la familia original. Usando la secuenciación del exoma, ahora identificamos un homocigoto. variante sin sentido (p.Gln517ter) en el último exón de un gen adyacente, el gen de la polinucleótido quinasa 3′-fosfatasa (PNKP). Artículo codifica una proteína de reparación del ADN recientemente asociada con ataxia recesiva con apraxia oculomotora tipo 4 (AOA4) y microcefalia, convulsiones y retraso del desarrollo (MCSZ). Posteriormente, cinco sujetos costarricenses CMT2 no relacionados inicialmente identificados como Se descubrió que ser heterocigoto para la misma variante MED25 también era heterocigoto compuesto para PNKP. Todos eran heterocigotos para la misma variante encontrada homocigota en la familia numerosa y una segunda previamente asociada con la ataxia (p.Thr408del). La reevaluación clínica detallada de la familia inicial y de los nuevos individuos reveló en todos un inicio en la edad adulta lentamente progresivo. CMT2 asociada con signos de disfunción cerebelosa como dificultad para hablar y afectación oculomotora, pero ni microcefalia, convulsiones ni retraso en el desarrollo. Proponemos que las variantes PKNP son la principal variante causante de la CMT2. fenotipo en estos individuos y que la manifestación clínica más leve se debe a un efecto alélico.Universidad Nacional, Costa RicaEscuela de Ciencias Biológica

Clinical and electrophysiological characteristics of autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2B) that maps to chromosome 19q13.3

Artículo científico -- 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::Vicerrectoría de Investigación::Unidades de Investigación::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

artículo -- 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 Psicológicas ////UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA

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)