ABSTRACT
The human genome consists of 23 pairs of chromosomes that contain 20 000-25 000 genes. Genetic disorders can be caused by different mechanisms, and therefore the confirmation of a suspected diagnosis requires knowledge of the underlying defect, so that the correct test can be applied. Monogenic diseases are caused by disturbances in a single gene, and currently only targeted diagnostic testing is available following a specific clinical suspicion. Chromosomal disorders usually involve multiple genes, so that the symptoms are often less specific. Specialists in Medical Genetics FMH are trained in creating a clinical genetic differential diagnosis, requesting the according laboratory test, interpretating the results and providing expert genetic counseling in presymptomatic and prenatal diagnosis. In Switzerland, specific legal principles and ethical guidelines must be taken into account.
Le génome humain est constitué de 23 paires de chromosomes et contient 20 000 à 25 000 gènes. Les maladies génétiques peuvent être causées par différents mécanismes, or pour confirmer un diagnostic présumé et utiliser le test adéquat, il est nécessaire de connaître le défaut génétique sous-jacent. Les maladies monogéniques sont causées par des perturbations dans un seul gène, et actuellement seul un test diagnostique ciblé peut être réalisé suite à une suspicion clinique spécifique. Les anomalies chromosomiques impliquent généralement plusieurs gènes, donc les symptômes sont souvent moins spécifiques. Les spécialistes en génétique médicale FMH sont formés à reconnaître cliniquement les diagnostics génétiques, à demander les analyses correspondantes, à en interpréter les résultats et à donner un conseil génétique adapté en diagnostic présymptomatique et prénatal. En Suisse, des principes juridiques et éthiques spécifiques doivent également être pris en compte.
Subject(s)
Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , Genetics, Medical/methods , Chromosome Aberrations , DNA Methylation/genetics , DNA Mutational Analysis/methods , Genetic Markers/genetics , Humans , In Situ Hybridization, Fluorescence , Karyometry/methods , Multiplex Polymerase Chain Reaction/methods , Oligonucleotide Array Sequence Analysis , Sequence Analysis, DNA , SwitzerlandABSTRACT
The vertebrate hindbrain is transiently divided along the anterior-posterior axis into seven morphologically and molecularly distinct segments, or rhombomeres, that correspond to Hox expression domains. The establishment of a proper 'hox code' is required for the development of unique rhombomere identities, including specification of neuronal fates. valentino (val), the zebrafish ortholog of mafB/Kreisler (Kr), encodes a bZip transcription factor that is required cell autonomously for the development of rhombomere (r) 5 and r6 and for activation of Hox group 3 gene expression. Recent work has demonstrated that the expression of val itself depends on three factors: retinoic acid (RA) signals from the paraxial mesoderm; fibroblast growth factor (Fgf) signals from r4; and variant hepatocyte nuclear factor 1 (vhnf1, also known as tcf2), a homeodomain transcription factor expressed posterior to the r4-5 boundary. We have investigated the interactions between these inputs onto val expression in the developing zebrafish hindbrain. We show that RA induces val expression via activation of vhnf1 expression in the hindbrain. Fgf signals from r4, acting through the MapK pathway, then cooperate with Vhnf1 to activate val expression and subsequent r5 and r6 development. Additionally, vhnf1 and val function as part of a multistep process required for the repression of r4 identity in the posterior hindbrain. vhnf1 acts largely independently of val to repress the r4 'hox code' posterior to the r4-5 boundary and therefore to block acquisition of r4-specific neuronal fates in the posterior hindbrain. However, vhnf1 is not able to repress all aspects of r4 identity equivalently. val is required downstream of vhnf1 to repress r4-like cell-surface properties, as determined by an 'Eph-ephrin code', by repressing ephrin-B2a expression in r5 and r6. The different requirements for vhnf1 and val to repress hoxb1a and ephrin-B2a, respectively, demonstrate that not all aspects of an individual rhombomere's identity are regulated coordinately.
