Genes modificadores en enfermedades poliglutamínicas.

Las enfermedades poliglutamínicas constituyen un grupo creciente de enfermedades neurodegenerativas humanas, causadas por la expansión de secuencias repetitivas de CAG que son traducidas para dar lugar a proteínas con dominios poliglutamínicos expandidos. La edad de inicio es un marcador fenotípico para estas enfermedades, y muestra una gran variación en  las familias afectadas. El número de repeticiones de CAG contenido en los genes causales, explica entre el 47 y 80% de la variabilidad observada en la edad de inicio. Para explicar la varianza restante ha sido propuesta la hipótesis de la existencia de genes modificadores. Aquí realizamos una revisión actualizada acerca de esta temática, abordando las estrategias más usadas para su identificación, los principales hallazgos obtenidos y sus implicaciones. La identificación de estos genes contribuye al esclarecimiento de los mecanismo patológicos involucrados en estas enfermedades, y puede conducir a la proposición y diseño de estrategias terapéuticas potenciales

GENES MODIFICADORES EN ENFERMEDADES POLIGLUTAMÍNICAS Modifying genes in poliglutaminic diseases

Las enfermedades poliglutamínicas constituyen un grupo creciente de enfermedades neurodegenerativas humanas, causadas por la expansión de secuencias repetitivas de CAG que son traducidas para dar lugar a proteínas con dominios poliglutamínicos expandidos. La edad de inicio es un marcador fenotípico para estas enfermedades, y muestra una gran variación en las familias afectadas. El número de repeticiones de CAG contenido en los genes causales, explica entre el 47 y 80% de la variabilidad observada en la edad de inicio. Para explicar la varianza restante ha sido propuesta la hipótesis de la existencia de genes modificadores. Aquí realizamos una revisión actualizada acerca de esta temática, abordando las estrategias más usadas para su identificación, los principales hallazgos obtenidos y sus implicaciones. La identificación de estos genes contribuye al esclarecimiento de los mecanismo patológicos involucrados en estas enfermedades, y puede conducir a la proposición y diseño de estrategias terapéuticas potenciales.<br>Poliglutaminic diseases are an increasing group of human neurodegenerative diseases caused by the expansion of repetitive sequences of CAG which give way to expanded poliglutaminic domains proteins. Ages of onset are a phenotypic marker for these diseases and show a great variation in the affected families. The number of CAG content repetitions in the causal genes, explains a 47 to 80 % of the variability of the age of onset. To explain the remaining variability, the hypothesis of modifying genes has been proposed. We have performed an updated revision of the the subject approaching the more utilized techniques to its identification, the principal findings and its implications. The identification of these genes contribute to clarify the involved pathological mechanisms in these diseases and might conduct to the proposition of potential therapeutic strategies

Novel Xp21.1 deletion associated with unusual features in a large McLeod syndrome kindred

McLeod syndrome (MLS) is a rare adult-onset, progressive and incurable X-linked multisystemic disorder characterized by chorea, cognitive decline, seizures, polyneuropathy, myopathy and dilated cardiomyopathy with subsequent heart failure and increased risk for arrhythmia [1]. Variable psychiatric symptoms are common; the presence of acanthocytes on blood smears, elevated CK levels and striatal atrophy are other features. MLS is caused by mutation in the XK gene which encodes a membrane transport protein containing the Kx erythrocyte antigen [1]. So far, less than 200 MLS cases have been reported. In general, women harboring XK mutations rarely manifest symptoms. In addition, myoclonus has not been described in association with MLS and functional imaging studies are scarce

Meta-analyses for large and intermediate CAG lengths in <i>ATXN2</i>.

<p>Galbraith (A–C) and forest plots (D–F) for different <i>ATXN2</i> CAG length across populations. A) and D) ≥24/27 CAG. B) and E) ≥30 CAG. C) and F) ≥32 CAG.</p

<i>De Novo</i> Mutations in Ataxin-2 Gene and ALS Risk

<div><p>Pathogenic CAG repeat expansion in the ataxin-2 gene (<i>ATXN2</i>) is the genetic cause of spinocerebellar ataxia type 2 (SCA2). Recently, it has been associated with Parkinsonism and increased genetic risk for amyotrophic lateral sclerosis (ALS). Here we report the association of <i>de novo</i> mutations in <i>ATXN2</i> with autosomal dominant ALS. These findings support our previous conjectures based on population studies on the role of large normal <i>ATXN2</i> alleles as the source for new mutations being involved in neurodegenerative pathologies associated with CAG expansions. The <i>de novo</i> mutations expanded from ALS/SCA2 non-risk alleles as proven by meta-analysis method. The ALS risk was associated with SCA2 alleles as well as with intermediate CAG lengths in the <i>ATXN2</i>. Higher risk for ALS was associated with pathogenic CAG repeat as revealed by meta-analysis.</p></div

Genetic markers for <i>ATXN2</i> haplotyping and gene sequencing.

<p>A) <i>ATXN2</i> gene schematic maps and microsatellite, D12S1333 (telomeric at 200 kb from <i>ATXN2</i>), D12S1672 (intragenic at exon 1) and D12S1332 (centromeric at 350 kb from <i>ATXN2</i>) and SNIPs markers, rs695871 (at 177 bp upstream CAG expansion), rs695872 (at 106 bp upstream CAG expansion) and rs390624 (within the expanded CAG) used for haplotyping cases involved in <i>de novo</i> mutations, the polymorphic (CCG)nCCC/poly-proline adjacent to the CAG expansion is also indicated. B) Sequencing for case II-10, mother of the proband III-16 (25 CAG with only one CAA interruption). C) Relative position for other SNPs situated either within or near the expanded CAG.</p

General mechanisms for <i>ATXN2</i> gene <i>de novo</i> mutagenesis in the population.

<p>Two models can be proposed for explanation of <i>de novo</i> CAG expansions in <i>ATXN2</i>. Both involve loss of the CAA interruption in large alleles resulting in a minimal length of pure repeat within the CAG expansion. CAA interruptions break the CAG tract in discrete repeat arrays protecting it from instability <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070560#pone.0070560-Ross1" target="_blank">[17]</a>. According to this study, the minimal length of the internal pure repeat leading to <i>de novo</i> mutations is 8 CAG.</p

Table. 2. Microsatellite haplotypes.

<p>NA: Not available, Inferred haplotype are bracketed,</p>*<p>sick by history.</p

Genetics, EMG and MRI analysis.

<p>A) Electrophoresis of fluorescent fragment analysis of <i>ATXN2</i> CAG repeat. In each lane, the content is specified. B) Fasciculation patterns in proband’s tongue and in biceps brachii recorded by EMG. C) Midsagittal MRI image of proband, no cerebellar atrophy is evident. D) Representative 3% agarose electrophoresis of <i>C9ORF72</i> analysis in index case and parents (lanes 2, 3, 4). Lanes 1and 8: MW markers (Ready Load™ 1–12.216 Kb ladder and 250–3500 bp ladder in multiples of 250 bp (Invitrogen), respectively; Lane 7: mock; lanes 2, 3, 4: case III-16, and both parents II-9 and II-10, respectively. Note that each DNA showed two defined bands despite PCR products with 7-deaza-2-deoxy GTP stain poorly with ethidium bromide. These 3 samples were heterozygous with bands higher than 250 bp but bellow 350 bp (hex repeat ∼11units) using Renton et al. primers anchoring 280 bp from hex-repeat. Lanes 5, 6 are unrelated ALS cases from the Cuban population.</p