Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Nonlinear optical properties and application of a chiral and photostimulable iron(II) compound

We measure linear absorption, circular dichroïsm, second harmonic and sum frequency generation in the [-Fe(phen) 3 ](Δ-As 2 (tartarate) 2), [-Fe(phen) 3 ](-As 2 (tartarate) 2) enantiomers of an Fe(II) complex. In the solid state, the chirality of this compound results from the introduction of the (As 2 (tartarate) 2) chiral anions. Linear absorption and X-ray diffraction indicate that Fe(II) is in the low-spin state. Circular dichroïsm reveals that in the solid state, these compounds are chiral, whereas the complexes racemize in solution. A large second harmonic generation signal is recorded using thin films from these two enantiomers. The second-order susceptibility of these compounds is evaluated across the visible spectral range. It displays a resonance at 520 nm, which is associated with the metal-to-ligand charge transfer occurring within the complex. At its maximum, = 6.4 pm V-1 is more than 1.4 times larger than the well-known beta-BaB 2 O 4 nonlinear crystal (~4.4 pm V-1). Finally, we demonstrate a useful application for a thin film from this compound, which characterizes the cross-correlation of two femtosecond laser pulses

Design and study of structural linear and nonlinear optical properties of Chiral [Fe(phen)3] 2+ complexes

The dependence of nonlinear optical properties upon the spin state in molecular switches is still an unexplored area. Chiral [Fe( phen)3]2+ complexes are excellent candidates for those studies because they are expected to show nonlinear optical properties of interest and at the same time show photoconversion to a short-lived metastable high-Spin state by ultrafast optical pumping. Herein, we present the synthesis, crystallographic, and spectroscopic comparison of chiral [Fe( phen)3]2+ complexes obtained with chiral anions, a new lipophilic derivative of the D2-symmetric (As2(tartrate)2)2-, and D3-symmetric tris(catechol)phosphate(V) (TRISCAT), tris(catechol)arsenate(V) (TRISCAS), and 3,4,5,6-tetrachlorocatechol phosphate(V) (TRISPHAT). Complexes [Fe( phen)3]( rac-TRISCAT)2 (2) and [Fe( phen)3](X-TRISCAS)2 (X = rac (3), Δ (4), Λ (5)) were found to be isomorphous in the R32 Sohncke space group with twinning by inversion correlated with the starting chiral anion optical purity. The structures show the [Fe( phen)3]2+ complex interacting strongly along its 3-fold axis with two anions. Only the structure of a [Fe( phen)3]( rac-TRISPHAT)2 solvate (6) could be obtained, which showed no particular anion/cation interaction contrary to what was observed previously in solution. The [Fe( phen)3](X-As2(tartrate)2) (X = Δ (7), Λ (8), and racemic mixture (9)) crystallizes in enantiomorphic space groups P3121/ P3221 with the same solid-state packing. Dichroic electronic absorption studies evidenced racemization for all chiral complexes in solution due to ion pair dissociation, whereas the asymmetric induction is conserved in the solid state in KBr pellets. We evidenced on chiral complexes 4 and 5 strong nonlinear second harmonic generation, the intensity of which could be correlated with the complex electronic absorption.Synthèse, caractérisation et mesures Optiques sur composés CHIRaux à Transition de Spi

A network of PDZ-containing proteins regulates T cell polarity and morphology during migration and immunological synapse formation

T cell shape is dictated by the selective recruitment of molecules to different regions of the cell (polarity) and is integral to every aspect of T cell function, from migration to cytotoxicity. This study describes a mechanism for the regulation of T cell polarity. We show that T cells contain a network of asymmetrically distributed proteins with the capacity to dictate the subcellular localization of both cell surface receptors and morphological determinants in T cells. Proteins from the Scribble, Crumbs3, and Par3 complexes, previously shown to regulate epithelial polarity, were polarized in T cells containing either uropods or immunological synapses. Reduction in Scribble expression prevented the polarization of cell surface receptors and prevented morphological changes associated with uropod formation, migration, and antigen presentation. By dynamically coordinating molecular distribution throughout the T cell, this network provides a mechanism by which T cell function and polarity are linked

Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective: To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.