"Refined mapping of a quantitative trait locus on chromosome 1 responsible for mouse embryonic death"

Recurrent spontaneous abortion (RSA) is defined as the loss of three or more consecutive pregnancies during the first trimester of embryonic intrauterine development. This kind of human infertility is frequent among the general population since it affects 1 to 5% of women. In half of the cases the etiology remains unelucidated. In the present study, we used interspecific recombinant congenic mouse strains (IRCS) in the aim to identify genes responsible for embryonic lethality. Applying a cartographic approach using a genotype/phenotype association, we identified a minimal QTL region, of about 6 Mb on chromosome 1, responsible for a high rate of embryonic death (,30%). Genetic analysis suggests that the observed phenotype is linked to uterine dysfunction. Transcriptomic analysis of the uterine tissue revealed a preferential deregulation of genes of this region compared to the rest of the genome. Some genes from the QTL region are associated with VEGF signaling, mTOR signaling and ubiquitine/proteasome-protein degradation pathways. This work may contribute to elucidate the molecular basis of a multifactorial and complex human disorder as RSA.

"Genome-Wide Linkage in a Highly Consanguineous Pedigree Reveals Two Novel Loci on Chromosome 7 for Non-Syndromic Familial Premature Ovarian Failure"

Background: The human condition known as Premature Ovarian Failure (POF) is characterized by loss of ovarian function before the age of 40. A majority of POF cases are sporadic, but 10–15% are familial, suggesting a genetic origin of the disease. Although several causal mutations have been identified, the etiology of POF is still unknown for about 90% of the patients. Methodology/Principal Findings: We report a genome-wide linkage and homozygosity analysis in one large consanguineous Middle-Eastern POF-affected family presenting an autosomal recessive pattern of inheritance. We identified two regions with a LODmax of 3.26 on chromosome 7p21.1-15.3 and 7q21.3-22.2, which are supported as candidate regions by homozygosity mapping. Sequencing of the coding exons and known regulatory sequences of three candidate genes (DLX5, DLX6 and DSS1) included within the largest region did not reveal any causal mutations. Conclusions/Significance: We detect two novel POF-associated loci on human chromosome 7, opening the way to the identification of new genes involved in the control of ovarian development and function.

Refined mapping of a quantitative trait locus on chromosome 1 responsible for mouse embryonic death

Recurrent spontaneous abortion (RSA) is defined as the loss of three or more consecutive pregnancies during the first trimester of embryonic intrauterine development. This kind of human infertility is frequent among the general population since it affects 1 to 5% of women. In half of the cases the etiology remains unelucidated. In the present study, we used interspecific recombinant congenic mouse strains (IRCS) in the aim to identify genes responsible for embryonic lethality. Applying a cartographic approach using a genotype/phenotype association, we identified a minimal QTL region, of about 6 Mb on chromosome 1, responsible for a high rate of embryonic death (similar to 30%). Genetic analysis suggests that the observed phenotype is linked to uterine dysfunction. Transcriptomic analysis of the uterine tissue revealed a preferential deregulation of genes of this region compared to the rest of the genome. Some genes from the QTL region are associated with VEGF signaling, mTOR signaling and ubiquitine/proteasome-protein degradation pathways. This work may contribute to elucidate the molecular basis of a multifactorial and complex human disorder as RSA.

Correlación genotipo-fenotipo y análisis molecular en pacientes con síndrome Down

El síndrome Down (SD) es la trisomía más común en humanos, presentándose en 1 de cada 745 nacidos vivos y es la causa más frecuente de retardo mental. El origen más observado de la trisomíaes una no disyunción meiótica (95%), la cual generalmente es de origen materno, mientras un 5% se debe a errores post-cigóticos mitóticos. Objetivo: identificar el origen parental delcromosoma 21 extra, el momento del error no disyuncional y establecer una correlación entre estos eventos y las manifestaciones fenotípicas de los pacientes afectados. Materiales y métodos: se estudiaron cincuenta familias con un hijo con SD mediante el uso de cinco short tandem repeats (STR) a lo largo de 21q, se construyeron los haplotipos de cada paciente y sus padres, determinandoel origen parental y el momento en que surgió el error no disyuncional. Resultados:en 80% de las familias el error fue en meiosis I y 20% en la meiosis II; 98% de los cromosomasadicionales fue de origen materno y 2% paterno. Se encontró correlación genotipo-fenotipo en ocho características estudiadas: cuello corto y ancho, tercera fontanela, labio inferior prominente, paladar estrecho y corto, raíz del hélix cruzando la concha, alopecia, pliegue único palmar yotras anomalías como nevus y xeroderma y eventos de recombinación en 24,5% de las familias analizadas. Conclusiones: la edad materna y la variación en el número de recombinaciones está asociada con no disyunciones meióticas I y II; se encontró correlación entre el momento del errorno disyuncional y algunas variables clínicas.