Biology subjects

Kraus, C.

Publications and source records attributed to Kraus, C..

3 recordsLinked to original sources

bioRxiv2018

The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy

BackgroundThe TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A.\n\nResultsIn three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G>A, p.(Gly436Asp) variant was novel, the two variants c.518C>T, p.(Pro173Leu) and c.641G>A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (70%), although reporting was incomplete in the different studies. We identified a total of 121 distinct variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein modelling, 38.6% of all disease causing variants including those in the C-terminal region are predicted to affect binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication.\n\nConclusionsWith 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.

genetics↗

bioRxiv2018

Need for high-resolution Genetic Analysis in iPSC: Results and Lessons from the ForIPS Consortium

Genetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines. In the majority, somatic copy number variants (CNVs) were identified. A subset with available matched donor DNA was selected for comparative exome sequencing. We identified single nucleotide variants (SNVs) at different allelic frequencies in each clone with high variability in mutational load. Low frequencies of variants in parental fibroblasts highlight the importance of germline samples. Somatic variant number was independent from reprogramming, cell type and passage. Comparison with disease genes and prediction scores suggest biological relevance for some variants. We show that high-throughput sequencing has value beyond SNV detection and the requirement to individually evaluate each clone.

genomics↗

bioRxiv2017

Differences in the genetic control of early egg development and reproduction between C. elegans and its parthenogenetic relative D. coronatus

BackgroundThe free-living nematode Diploscapter coronatus is the closest known relative of C. elegans with parthenogenetic reproduction. It shows several developmental idiosyncracies, for example concerning the control of meiosis and embryonic axis formation [1]. Our recent genome analysis [2] provided some support for the view that D. coronatus is a product of interspecies hybridization. Here we present additional data towards this assumption. Based on genomic and transcriptomic data we try to better understand the molecular basis of developmental idiosyncrasies in this species in an evolutionary context by comparison with selected other nematodes.\n\nResultsIn a genomic comparison between D. coronatus, C. elegans, other representatives of the genus Caenorhabditis and the more distantly related Pristionchus pacificus and Panagrellus redivivus, certain genes required for normal embryogenesis in C. elegans were found to be restricted to the genus Caenorhabditis. The mRNA content of early D. coronatus embryos was sequenced and compared with similar stages in C. elegans and Ascaris suum. We identified 350 gene families transcribed in the early embryo of D. coronatus but not in the other two nematodes. Looking at individual genes transcribed early in D. coronatus but not in C. elegans and A. suum we found that orthologs of most of these are present in the genomes of the latter species as well, suggesting heterochronic shifts with respect to expression behavior. Considerable divergence between alleles lends further support to the view that D. coronatus may be the result of an interspecies hybridization. Expression analysis of early acting single copy genes yield no indication for silencing of one parental genome.\n\nConclusionsOur comparative cellular and molecular studies support the view that the genus Caenorhabditis differs considerably from the other studied nematodes in its control of development and reproduction. The easy-to-culture parthenogenetic D. coronatus, with its high quality draft genome and only a single chromosome when haploid, offers many new starting points on the cellular, molecular, and genomic level to better understand alternative routes of nematode development and reproduction.

evolutionary biology↗