[Molecular medicine: pathobiochemistry as the key to personalized treatment of inherited diseases]. / Molekulare Medizin: Pathobiochemie als Schlüssel zur personalisierten Therapie vererbter Krankheiten.

Genetic defects are often still regarded as a life-long fate, which one has to cope with. It is true that in many cases an inherited disposition may lead to a severe disease; however, it is also true that the number of genetic defects with a treatment option is continuously increasing and in some of them the onset of disease symptoms can even be totally prevented. Knowledge of the precise molecular pathomechanism is often the basis for a treatment concept. Genome-wide sequencing has tremendously increased the possibility to identify a genetic defect and its broad application has meanwhile made a decisive contribution in routine diagnostics. After identifying a genetic alteration, it is still necessary to investigate the pathobiochemical consequences on the cellular and systemic level. This can be a time-consuming process since not all functional consequences can be immediately recognized. In the case of metabolic defects the treatment strategy can either be a supplementation of missing products or a removal of toxic substrates. The residual function of affected pathways can also often be improved. Recently, the direct correction of the affected genetic defects has become a treatment option for a selected number of diseases. As the first symptoms of disease usually occur early in life, pediatrics has a pioneering role in developing treatment strategies.

Lack of complex I is associated with oncocytic thyroid tumours.

Oncocytic tumours are characterised by hyperproliferation of mitochondria. We immunohistochemically analysed all enzymes of the oxidative phosphorylation system in 19 oncocytic thyroid tumours. A specific lack of complex I was detected, which was expressed at <5% of the level determined in surrounding non-cancerous tissue.

Complexity of developmental control: analysis of embryonic cell lineage specification in Caenorhabditis elegans using pes-1 as an early marker.

In the early Caenorhabditis elegans embryo five somatic founder cells are born during the first cleavages. The first of these founder cells, named AB, gives rise to 389 of the 558 nuclei present in the hatching larva. Very few genes directly involved in the specification of the AB lineage have been identified so far. Here we describe a screen of a large collection of maternal-effect embryonic lethal mutations for their effect on the early expression of a pes-1::lacZ fusion gene. This fusion gene is expressed in a characteristic pattern in 14 of the 32 AB descendants present shortly after the initiation of gastrulation. Of the 37 mutations in 36 genes suspected to be required specifically during development, 12 alter the expression of the pes-1::lacZ marker construct. The gene expression pattern alterations are of four types: reduction of expression, variable expression, ectopic expression in addition to the normal pattern, and reduction of the normal pattern together with ectopic expression. We estimate that approximately 100 maternal functions are required to establish the pes-1 expression pattern in the early embryo.

mex-1 and the general partitioning of cell fate in the early C. elegans embryo.

It is thought that at least some of the initial specification of the five somatic founder cells of the C. elegans embryo occurs cell-autonomously through the segregation of factors during cell divisions. It has been suggested that in embryos from mothers homozygous for mutations in the maternal-effect gene mex-1, four blastomeres of the 8-cell embryo adopt the fate of the MS blastomere. It was proposed that mex-1 functions to localise or regulate factors that determine the fate of this blastomere. Here, a detailed cell lineage analysis of 9 mex-1 mutants reveals that the fates of all somatic founder cells are affected by mutations in this gene. We propose that mex-1, like the par genes, is involved in establishing the initial polarity of the embryo.