PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T&gt;G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C&gt;A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.</p

Paternal lineage of the Berbers from Aurès in Algeria: estimate of their genetic variation

Background: Aurès is a vast territory in the east of Algeria, characterised by its traditional Berber settlement which has preserved its language and its rich history; its name goes back to antiquity and before the Roman conquest it was part of the territory of ancient Numidia. The Chaoui people in this region are one of Algeria’s largest Berber groups. Aim: The aims were to investigate the level of genetic diversity of the Berbers of Aurès through the analysis of the paternal gene pool and to estimate the percentage of genetic variation among different geographical regions and linguistic groups from Algeria. Subjects and methods: Twenty-three Y-STRs were genotyped in a sample of 218 unrelated males of the Berbers of Aurès. Algorithms were used to estimate the Y-chromosome haplogroups. Genetic distance, non-metric MDS and AMOVA were used to analyse the genetic relationships between sample groups. Results: The paternal lineage of this sample of the Aurès region did not exhibit strong signals of differentiation with other samples from North-central, Northwest, and South Algeria. However, significant differences were found within this sample, demonstrating a high degree of heterogeneity. Conclusion: The results demonstrate that Aurès people are isolated and closed, but nevertheless have quite different genetic profiles

Genetic diversity of 15 autosomal STRs in a sample of Berbers from Aurès region in the Northeast of Algeria and genetic relationships with other neighbouring samples

Background: The history of the Aurès mountains and neighbouring areas, a large region of the East of Algeria, was part of the history of the ancient independent Berber kingdoms supposed to be the ancestors of the current Berber people. The genetic background of this region has not yet been clarified. Aim: The aims of our study were to investigate the genetic characteristics of 15 autosomal short tandem repeats (STRs) in a sample from these regions, to determine the degree of heterogeneity among Algerian and North African samples and to analyse the genetic relationships with other populations. Subjects and methods: Allele frequencies, forensic parameters and Hardy–Weinberg equilibrium (HWE) of 15 autosomal STRs included in the PowerPlex® ESI 16 System were obtained from 308 individuals. Allele frequencies were used to determine the relationships with other populations. Results: All loci were highly polymorphic and no significant deviation from HWE was detected. Allele frequencies showed that the samples of Aurès region share genetic affinities with other Algerian, North African and Middle Eastern samples, with the exception of samples from Iran and Matmata. Conclusions: These markers revealed a genetic homogeneity between the Algerian and North African samples. The genetic affinities indicate that this sample could share a common ancestor with the Middle Eastern samples

Interaction of an IHF-like protein with the Rhizobium etli nifA promoter.

The nifA gene fulfills an essential role in the regulation of nitrogen fixation genes in Rhizobium etli. Transcription analysis of the nifA gene, assessed using promoter deletions, indicated an oxygen-independent expression, threefold higher during symbiosis as compared with free-living conditions. Electrophoretic mobility shift assays using those nifA promoter deletion fragments, which were actively transcribed, demonstrated the specific interaction with R. etli cellular protein(s) resulting in the formation of two DNA-protein complexes. An interacting protein was purified by liquid chromatography on Heparin Sepharose and Mono S columns. The purified 12 kDa R. etli protein cross-reacted with antibodies directed against Escherichia coli integration host factor (IHF). Furthermore, purified E. coli IHF was able to specifically bind to the R. etli nifA promoter region. These results point to an as yet undisclosed function of IHF in the regulation of R. etli nifA expression.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

The complex translocation (9;14;14) involving IGH and CEBPE genes suggests a new subgroup in B-lineage acute lymphoblastic leukemia

Abstract Many subtypes of acute lymphoblastic leukemia (ALL) are associated with specific chromosomal rearrangements. The complex translocation t(9;14;14), a variant of the translocation (14;14)(q11;q32), is a rare but recurrent chromosomal abnormality involving the immunoglobulin heavy-chain (IGH) and CCAAT enhancer-binding protein (CEBPE) genes in B-lineage ALL (B-ALL) and may represent a new B-ALL subgroup. We report here the case of a 5-year-old girl with B-ALL, positive for CD19, CD38 and HLA-DR. A direct technique and G-banding were used for chromosomal analysis and fluorescentin situ hybridization (FISH) with BAC probes was used to investigate a possible rearrangement of the IGH andCEBPE genes. The karyotype exhibit the chromosomal aberration 46,XX,del(9)(p21),t(14;14)(q11;q32). FISH with dual-color break-apartIGH-specific and CEPBE-specific bacterial artificial chromosome (BAC) probes showed a complex t(9;14;14) associated with a deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A) and paired box gene 5 (PAX5) at 9p21-13 and duplication of the fusion gene IGH-CEBPE

Whole mitogenomes reveal that NW Africa has acted both as a source and a destination for multiple human movements

Despite being enclosed between the Mediterranean Sea and the Sahara Desert, North Africa has been the scenario of multiple human migrations that have shaped the genetic structure of its present-day populations. Despite its richness, North Africa remains underrepresented in genomic studies. To overcome this, we have sequenced and analyzed 264 mitogenomes from the Algerian Chaoui-speaking Imazighen (a.k.a. Berbers) living in the Aurès region. The maternal genetic composition of the Aurès is similar to Arab populations in the region, dominated by West Eurasian lineages with a moderate presence of M1/U6 North African and L sub-Saharan lineages. When focusing on the time and geographic origin of the North African specific clades within the non-autochthonous haplogroups, different geographical neighboring regions contributed to the North African maternal gene pool during time periods that could be attributed to previously suggested admixture events in the region, since Paleolithic times to recent historical movements such as the Arabization. We have also observed the role of North Africa as a source of geneflow mainly in Southern European regions since Neolithic times. Finally, the present work constitutes an effort to increase the representation of North African populations in genetic databases, which is key to understand their history.This work was supported by the Spanish Ministry of Science and Innovation (Grant Number PID2019-106485GB-I00) and “Unidad María de Maeztu” (CEX2018-000792-M) funded by the MCIN and the AEI (https://doi.org/10.13039/501100011033)

The impact of recent demography on functional genetic variation in north african human groups

The strategic location of North Africa has made the region the core of a wide range of human demographic events, including migrations, bottlenecks, and admixture processes. This has led to a complex and heterogeneous genetic and cultural landscape, which remains poorly studied compared to other world regions. Whole-exome sequencing is particularly relevant to determine the effects of these demographic events on current-day North Africans' genomes, since it allows to focus on those parts of the genome that are more likely to have direct biomedical consequences. Whole-exome sequencing can also be used to assess the effect of recent demography in functional genetic variation and the efficacy of natural selection, a long-lasting debate. In the present work, we use newly generated whole-exome sequencing and genome-wide array genotypes to investigate the effect of demography in functional variation in 7 North African populations, considering both cultural and demographic differences and with a special focus on Amazigh (plur. Imazighen) groups. We detect genetic differences among populations related to their degree of isolation and the presence of bottlenecks in their recent history. We find differences in the functional part of the genome that suggest a relaxation of purifying selection in the more isolated groups, allowing for an increase of putatively damaging variation. Our results also show a shift in mutational load coinciding with major demographic events in the region and reveal differences within and between cultural and geographic groups.This work was supported by the Spanish Ministry of Science and Innovation (grant numbers I-COOP0018, PID2019-106485GB-I00, and PID2022-138755NB-I00) and “Unidad María de Maeztu” (CEX2018-000792-M) funded by the MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”