Biology subjects

Palm, G.

Publications and source records attributed to Palm, G..

2 recordsLinked to original sources

bioRxiv2022

Molecular genetics of GLUT1DS Italian pediatric cohort: 10 novel related-disease variants and structural analysis

GLUT1 deficiency syndrome (GLUT1DS1; OMIM #606777) is a rare genetic metabolic disease, characterized by infantile-onset epileptic encephalopathy, global developmental delay, progressive microcephaly and movement disorders (e.g. spasticity and dystonia). It is caused by heterozygous mutations in the SLC2A1 gene, which encodes the GLUT1 protein, a glucose transporter across the blood-brain barrier (BBB). Most commonly these variants arise de novo resulting in sporadic cases, although several familial cases with AD inheritance pattern have been described. Twenty-seven Italian pediatric patients clinically suspect of GLUT1DS from both sporadic and familial cases have been enrolled. We detected by trios sequencing analysis 25 different variants causing GLUT1DS. Of these, 40% of the identified variants (10 out of 25) had never been reported before, including missense, frameshift and splice site variants. Their X-ray structure analyses strongly suggested the potential pathogenic effects of these novel disease-related mutations, broadening the genotypic spectrum heterogeneity found in the SLC2A1 gene. Moreover, 24% is located in a vulnerable region of the GLUT1 protein that involves transmembrane 4 and 5 helices encoded by exon 4, confirming a mutational hotspot in the SLC2A1 gene. Lastly, we investigated possible correlations between mutation type and clinical and biochemical data observed in our GLUT1DS cohort, revealing that splice site and frameshift variants are related to a more severe phenotype and low CSF parameters. Author summaryWe investigated the molecular data of 27 pediatric patients clinically suspect of GLUT1 deficiency syndrome. By performing trios sequencing analysis, we highlighted ten novel disease-related variants, and their X-ray structure analyses, suggesting the pathogenic effects of these identified mutations. Moreover, the wide clinical and genetic heterogeneity observed in our cohort allowed possible correlations between mutation type and clinical and biochemical data. This analysis enabled to delineate that splice site and frameshift variants are related to a more severe phenotype and low CSF/glucose values. Further clinical and genetic/epigenetics studies could clearly the high phenotypic variability observed in these patients.

genetics↗

bioRxiv2021

Generating surrogates for significance estimation ofspatio-temporal spike patterns

The generation of surrogate data, i.e., the modification of original data to destroy a certain feature, is used for the implementation of a null-hypothesis whenever an analytical approach is not feasible. Thus, surrogate data generation has been extensively used to assess the significance of spike correlations in parallel spike trains. In this context, one of the main challenges is to properly construct the desired null-hypothesis distribution and to avoid a bias in the null-hypothesis by altering the spike train statistics. A classical surrogate technique is uniform dithering (UD), which displaces spikes locally and uniformly. In this study, we compare UD against five surrogate techniques (two newly introduced) in the context of the detection of significant spatio-temporal spike patterns. We evaluate the surrogates for their performance, first on spike trains based on point process models with constant firing rate, and second on modeled non-stationary artificial data serving as ground truth to assess the pattern detection in a more complex and realistic setting. We determine which statistical features of the original spike trains are modified and to which extent. Moreover, we find that UD fails as an appropriate surrogate because it leads to a loss of spikes in the context of binning and clipping, and thus to a large number of false-positive patterns. The other surrogates achieve a better performance in detecting precisely timed higher-order correlations. Based on these insights, we analyze experimental data from pre-/motor cortex of macaque monkeys during a reaching-and-grasping task for spatio-temporal spike patterns. Significance statementTemporal jittering or dithering of single spikes or subsections of spike trains is a common method of generating surrogate data for the statistical analysis of temporal spike correlations. We discovered a serious problem with the classical and widely used method of uniform dithering that can lead to an overestimation of significance, i.e., to false positives in the statistical evaluation of spatio-temporal spike patterns. Therefore we consider 5 other dithering methods, compare and evaluate their statistical properties. Finally, we apply a much better method (trial shifting) to the analysis of experimental multiple-unit recordings and find several highly significant patterns that also reflect different experimental situations.

neuroscience↗