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Mutations in glycosylation pathways, such as N-linked glycosylation, O-linked glycosylation, and GPI anchor synthesis, lead to Congenital Disorders of Glycosylation (CDG). CDG typically present with seizures, hypotonia, and developmental delay but display large clinical variability with symptoms affecting every system in the body. This variability suggests modifier genes might influence the phenotypes. Because of the similar physiology and clinical symptoms, there are likely common genetic modifiers between CDG. Here, we use evolution as a tool to identify common modifiers between CDG and glycosylation genes. Protein glycosylation is evolutionarily conserved from yeast to mammals. Evolutionary rate covariation (ERC) identifies proteins with similar evolutionary rates that indicate shared biological functions and pathways. Using ERC, we identified strong evolutionary rate signatures between proteins in the same and different glycosylation pathways. Genome-wide analysis of proteins showing significant ERC with GPI anchor synthesis proteins revealed strong signatures with ncRNA modification proteins and DNA repair proteins. We also identified strong patterns of ERC based on cellular sub-localization of the GPI anchor synthesis enzymes. Functional testing of the highest scoring candidates validated genetic interactions and identified novel genetic modifiers of CDG genes. ERC analysis of disease genes and biological pathways allows for rapid prioritization of potential genetic modifiers, which can provide a better understanding of disease pathophysiology and novel therapeutic targets. Author summary: Congenital Disorders of Glycosylation (CDG) are a group of rare disorders resulting from impaired protein glycosylation. Glycosylation is the addition of sugar chains onto proteins and is required for proper protein function. CDG patients typically present with seizures and hypotonia. However, they can have a large amount of clinical variability, which is likely influenced by modifier genes. Modifier genes are genes that affect a phenotype without causing the disease. Using an evolutionary method that examines proteins that evolve at similar rates, we identified proteins within glycosylation pathways and among other unexpected pathways, such as ncRNA modification and DNA repair, that could be potential genetic modifiers of CDG genes. We also tested top protein pairs using the Drosophila eye as a model and identified novel genetic modifiers of CDG genes. Broadening our understanding of CDG modifiers can help us to better understand why loss of glycosylation results in specific patient symptoms and could provide new treatment targets. [ABSTRACT FROM AUTHOR]

Stress preconditioning occurs when transient, sublethal stress events impact an organism's ability to counter future stresses. Although preconditioning effects are often noted in the literature, very little is known about the underlying mechanisms. To model preconditioning, we exposed a panel of genetically diverse Drosophila melanogaster to a sublethal heat shock and measured how well the flies survived subsequent exposure to endoplasmic reticulum (ER) stress. The impact of preconditioning varied with genetic background, ranging from dying half as fast to 4 and a half times faster with preconditioning compared to no preconditioning. Subsequent association and transcriptional analyses revealed that histone methylation, and transcriptional regulation are both candidate preconditioning modifier pathways. Strikingly, almost all subunits (7/8) in the Set1/COMPASS complex were identified as candidate modifiers of preconditioning. Functional analysis of Set1 knockdown flies demonstrated that loss of Set1 led to the transcriptional dysregulation of canonical ER stress genes during preconditioning. Based on these analyses, we propose a preconditioning model in which Set1 helps to establish an interim transcriptional "memory" of previous stress events, resulting in a preconditioned response to subsequent stress. [ABSTRACT FROM AUTHOR]

Context: A genetic etiology accounts for the majority of unexplained primary ovarian insufficiency (POI). Objective: We hypothesized a genetic cause of POI for a sister pair with primary amenorrhea. Design: The study was an observational study. Subjects were recruited at an academic institution. Subjects: Subjects were sisters with primary amenorrhea caused by POI and their parents. Additional subjects included women with POI analyzed previously (n = 291). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233). Intervention: We performed whole exome sequencing, and data were analyzed using the Pedigree Variant Annotation, Analysis and Search Tool, which identifies genes harboring pathogenic variants in families. We performed functional studies in a Drosophila melanogaster model. Main Outcome: Genes with rare pathogenic variants were identified. Results: The sisters carried compound heterozygous variants in DIS3. The sisters did not carry additional rare variants that were absent in publicly available datasets. DIS3 knockdown in the ovary of D. melanogaster resulted in lack of oocyte production and severe infertility. Conclusions: Compound heterozygous variants in highly conserved amino acids in DIS3 and failure of oocyte production in a functional model suggest that mutations in DIS3 cause POI. DIS3 is a 3' to 5' exoribonuclease that is the catalytic subunit of the exosome involved in RNA degradation and metabolism in the nucleus. The findings provide further evidence that mutations in genes important for transcription and translation are associated with POI. [ABSTRACT FROM AUTHOR]

The nonsynonymous variants of lipid phosphatase (FIG4) in patients with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) is described. Heterozygosity for a deleterious allele FIG 4 that regulates PI(3,5)[P.sub.2] is found to be a risk factor for ALS and PLS, extending the list of known ALS genes and increasing the clinical spectrum of FIG4-related diseases.

Context: A genetic etiology likely accounts for the majority of unexplained primary ovarian insufficiency (POI). Objective: We hypothesized that heterozygous rare variants and variants in enhanced categories are associated with POI. Design: The study was an observational study. Setting: Subjects were recruited at academic institutions. Patients: Subjects from Boston (n = 98), the National Institutes of Health and Washington University (n = 98), Pittsburgh (n = 20), Italy (n = 43), and France (n = 32) were diagnosed with POI (amenorrhea with an elevated follicle-stimulating hormone level). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233). Intervention: We performed whole exome sequencing (WES), and data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. We performed functional studies on identified genes that were not previously implicated in POI in a D. melanogaster model. Main Outcome: Genes with rare pathogenic variants and gene sets with increased burden of deleterious variants were identified. Results: Candidate heterozygous variants were identified in known genes and genes with functional evidence. Gene sets with increased burden of deleterious alleles included the categories transcription and translation, DNA damage and repair, meiosis and cell division. Variants were found in novel genes from the enhanced categories. Functional evidence supported 7 new risk genes for POI (USP36, VCP, WDR33, PIWIL3, NPM2, LLGL1, and BOD1L1). Conclusions: Candidate causative variants were identified through WES in women with POI. Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI. [ABSTRACT FROM AUTHOR]