X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients

Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

La Farmacogenética y la Medicina individualizada

Artículos especialesThe last decade has seen rapid progress and development in the understanding of genetic influences that underlie inter-individual differences in drug action and drug response. Differences in DNA sequences that alter the expression or function of proteins that are targeted by drugs can contribute significantly to variation in the responses of individuals. Many of the genes examined so far are linked to highly penetrant, single-gene traits, but future advances are focused on the more difficult challenge of elucidating multigene determinants of drug response. The interaction of genomics and medicine has the potential to yield a new set of molecular diagnostic tools that can be used to individualize and optimize drug therapyN

Maintien et évolution des fréquences des anomalies de structures chromosomiques : application à quelques anomalies étudiées chez l'homme

Serre J.-L., Feingold J., Gallano P., BouÉ J. and Boue A. — The Maintenance and Evolution of the Frequence of Abnormalities in Chromosomal Structures. An Application to some Abnormalities in Man. The genetic information of any organism is contained in a stock of chromosomes, the number and structure of which are characteristics peculiar to the species. Within each species, and more particularly in man, numerous abnormalities in number or in structure (chromosomal modifications) have been described. Though they often lend to serious pathological consequences, the frequency of some abnormalities is not negligible and some of them even can be transmitted to later generations. The study of the frequency of such abnormalities and its development is interesting for two reasons : first to attempt a forecast which shows the effect on public health; secondly, to construct a model which would account for the possible role of these modifications in evolution. The model described in this article includes several causes which tend to a variation in frequencies : mutation (probability of new cases), selection (differential mortality or fertility of those affected) and segregationKlistorsion (non-Mendelian segregation of the abnormalities in the progeny of the healthy carriers). The model shows clearly that determinist processes such as selection or segregation distorsion can only play a part in evolution through their association with stochastic processes such as genetic drift or founder effect.Serre J.-Lm Feingold J., Gallano P., Boue J. et Воий А. — Maintien et évolution des fréquences des anomalies de structures chromosomiques : Application à quelques anomalies étudiées chez l'homme. L'information génétique de tout organisme est contenue dans un stock de chromosomes dont le nombre et la structure sont des caractéristiques propres à l'espèce. Au sein de chaque espèce, chez l'homme notamment, on a décrit de nombreuses anomalies de nombre ou de structure (remaniements chromosomiques). Bien qu'ayant souvent des conséquences pathologiques graves, quelques anomalies présentent des fréquences non négligeables et certaines d'entre elles sont même transmissibles aux générations ultérieures. L'étude du maintien ou de l'évolution de la fréquence de telles anomalies a un double intérêt: le premier, pratique, est de tenter une prévision en matière de Santé Publique; le second, théorique, tend à dégager un modèle pour rendre compte du rôle possible de ces remaniements dans l'évolution. Le modèle défini dans cet article intègre plusieurs causes de variation de fréquence : la mutation (probabilité d'apparition de novo), la sélection (mortalité ou fécondité différentielle des porteurs d'anomalies) et la distorsion de ségrégation (ségrégation non mendélienne des anomalies dans la descendance des porteurs sains). L'un des résultats de ce modèle est de montrer clairement que les processus déterministes comme la sélection ou la distorsion de ségrégation n'ont pu jouer un rôle, dans l'évolution des espèces, qu'en étant associés aux effets de processus stochastiques comme la dérive ou l'effet fondateur.Serre J.-L., Feingold J., Gallano P., BouÉ J. et Воий А. — Frecuencia у evolution de ciertas anomalies en las estructuras cromosómicas : estudio de algunos casos en la especie humana. La information genética de todo organismo esta contenida en su dotación de cromosomas cuyo numero у estructura constituyen características propias de cada especie. En el seno de cada especie, principalmente en el caso de la especie humana, se han observado numerosas anomalias tanto en el numero como en la estructura de los cromosomas (aberraciones cromosómicas). A menudo estas aberraciones acarrean consecuencias patológicas graves, sin embargo algunas de ellas presentan frecuencias que no son despreciables e incluso pueden ser transmisibles a las generaciones siguientes. El estudio de la presencia y evolución de taies anomalias ofrece un doble interés : el primero, práctico, es el de sugerir medidas de prevision en el campo de la Salud Publica; el segundo, teórico, tiende a establecer un modelo que pudiera explicar el papel que estas modificaciones pueden tener en la evolución. En el modelo que se présenta en este articule- se integran varias causas de estas frecuencias : mutación (probabilidad de la aparición de una modification que no existe en los padres), selection (mortalidad o fecundidad diferenciál de los portadores de tales anomalias) y distorsion de la segregation (segrecación de carácter no mendeliano de las anomalias en la descendencia de los portadores sanos). Uno de los resultados de este modelo es el de mostrar claramente que los procesos deterministas como la selection о la distorsion de la segregation no han podido ejercer un papel en la evolución de las especies, sino que en la medida en que estos factores se han asociado a los efectos de procesos estocásticos, como la dériva genético el efecto fundador.Serre J.-L., Feingold J., Gallano P., Boué Joëlle, Boue A. Maintien et évolution des fréquences des anomalies de structures chromosomiques : application à quelques anomalies étudiées chez l'homme. In: Population, 38ᵉ année, n°2, 1983. pp. 283-310

Linkage disequilibrium for DNA haplotypes near the cystic fibrosis locus in two south European populations

Three polymorphic DNA marker loci (INT1L1, D7S23 and D7S399) map to a chromosomal region that is very close to the cystic fibrosis (CF) locus in terms of genetic distance. These marker loci have been used to analyse the linkage disequilibrium in 137 CF families from two South European countries (Italy and Spain). The markers can be analysed for differences in linkage disequilibrium more easily in these populations than in North Europeans, in whom the disequilibrium between the allelic systems defined by the probes and CF is much greater and on a "plateau" through the genetic region. The different levels of disequilibrium found in the studied populations suggest that D7S399 and D7S23 are both closer to CF than INT1L1, and provide additional information on the origins and homogeneity of the CF defect

Abnormal expression of dysferlin in skeletal muscle and monocytes supports primary dysferlinopathy in patients with one mutated allele

Background: In some cases, a definitive confirmation of dysferlinopathy cannot be achieved by DNA test, because the mutation is detected in one allele only. Patients and methods: Dysferlin expression in skeletal muscle and peripheral blood monocytes (PBM) was studied by Western blot in two unrelated adult patients. The comparative CT method (ΔΔCT) was used to calculate relative changes in dysferlin mRNA determined from real-time quantitative PCR experiments. The dysferlin gene was studied by direct sequencing of cDNA and genomic DNA and by Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. Results: A comparable severe reduction in dysferlin was demonstrated in both skeletal muscle and PBM. The expression of dysferlin mRNA was significantly reduced. A novel mutation in exon 47 (c.5289G>C) of the dysferlin gene in the heterozygous state, causing an amino acid change (p.Glu1763Asp), was detected in both patients. The MLPA analysis did not reveal any deletion or duplication. Conclusions: Dysferlin and/or dysferlin mRNA abnormalities are diagnostic for dysferlinopathy when mutational analysis detects a mutation in one allele only. Analysis of dysferlin mRNA can be helpful for distinguishing symptomatic heterozygotes from such patients. © 2010 The Author(s). European Journal of Neurology © 2010 EFNS