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PubMed2026

Achromobacter species in cystic fibrosis and chronic lung disease: a review of virulence, antibiotic resistance, diagnostic challenges, and emerging therapies.

Achromobacter species (spp) is an emerging opportunistic organism more frequently isolated from immunocompromised patients' and hospital settings. This bacterium was once considered an environmental bacterium, but now it is recognized as a serious cause of respiratory infections, bloodstream infections, and urinary tract infections, particularly among patients with cystic fibrosis (CF), chronic illnesses, and medical devices. The purpose of this review is to highlight Achromobacte's clinical significance, pathogenic mechanism, and recent approaches for diagnosis and treatment. By utilizing specific keywords relevant to Achromobacter spp., a comprehensive literature search was performed in PubMed and Google Scholar. To summarize existing knowledge and highlight gaps in the literature, peer-reviewed studies on clinical relevance, pathogenicity, antimicrobial resistance, and therapeutic approaches were gathered, screened, and narratively assembled. Among the 19 identified species, Achromobacter xylosoxidans (A. xylosoxidans) is the most prevalent and clinically relevant, especially in CF settings. This review explores the organism's microbiological characteristics, virulence strategies-including robust biofilm formation, motility, and secretion systems-and its alarming intrinsic and acquired resistance to antibiotics. Misidentification due to phenotypic overlap with other non-fermenting Gram-negative bacilli complicates diagnosis, while limited MALDI-TOF MS and database representation hinders species-level identification. Genotyping methods, including multi-locus sequence analysis and housekeeping gene sequencing, offer superior resolution but remain underutilized in clinical diagnostics. With rising resistance mediated by β-lactamases, efflux pumps, and adaptive genomic traits, Achromobacter spp presents a growing challenge for treatment and infection control. This review highlights the urgent need for improved diagnostic strategies, species-level clinical and microbiological data, and tailored therapeutic approaches to manage Achromobacter spp. infections effectively.

Humans↗
PubMed2024

ASXL1 truncating variants in BOS and myeloid leukemia drive shared disruption of Wnt-signaling pathways but have differential isoform usage of RUNX3.

BACKGROUND: Rare variants in epigenes (a.k.a. chromatin modifiers), a class of genes that control epigenetic regulation, are commonly identified in both pediatric neurodevelopmental syndromes and as somatic variants in cancer. However, little is known about the extent of the shared disruption of signaling pathways by the same epigene across different diseases. To address this, we study an epigene, Additional Sex Combs-like 1 (ASXL1), where truncating heterozygous variants cause Bohring-Opitz syndrome (BOS, OMIM #605039), a germline neurodevelopmental disorder, while somatic variants are driver events in acute myeloid leukemia (AML). No BOS patients have been reported to have AML. METHODS: This study explores common pathways dysregulated by ASXL1 variants in patients with BOS and AML. We analyzed whole blood transcriptomic and DNA methylation data from patients with BOS and AML with ASXL1-variant (AML-ASXL1) and examined differential exon usage and cell proportions. RESULTS: Our analyses identified common molecular signatures between BOS and AML-ASXL1 and highlighted key biomarkers, including VANGL2, GRIK5 and GREM2, that are dysregulated across samples with ASXL1 variants, regardless of disease type. Notably, our data revealed significant de-repression of posterior homeobox A (HOXA) genes and upregulation of Wnt-signaling and hematopoietic regulator HOXB4. While we discovered many shared epigenetic and transcriptomic features, we also identified differential splice isoforms in RUNX3 where the long isoform, p46, is preferentially expressed in BOS, while the shorter p44 isoform is expressed in AML-ASXL1. CONCLUSION: Our findings highlight the strong effects of ASXL1 variants that supersede cell-type and even disease states. This is the first direct comparison of transcriptomic and methylation profiles driven by pathogenic variants in a chromatin modifier gene in distinct diseases. Similar to RASopathies, in which pathogenic variants in many genes lead to overlapping phenotypes that can be treated by inhibiting a common pathway, our data identifies common pathways for ASXL1 variants that can be targeted for both disease states. Comparative approaches of high-penetrance genetic variants across cell types and disease states can identify targetable pathways to treat multiple diseases. Finally, our work highlights the connections of epigenes, such as ASXL1, to an underlying stem-cell state in both early development and in malignancy.

Humans↗
PubMed2026

Phenotyping strategies for chronic overlapping pain conditions and internalizing disorders in Veterans: Prevalence, comorbidity, and latent structure as evidence for construct validity.

Chronic overlapping pain conditions (COPCs), internalizing (INT) disorders, and opioid use disorder (OUD) are common, comorbid, and difficult to phenotype at scale. Electronic health record (EHR) studies commonly define cases using Any Code (AC; ≥1 ICD-9/10 code) and Multiple Code (MC; ≥1 inpatient or ≥2 outpatient codes) phenotyping strategies, but it is unclear whether these thresholds change only case numbers or also the clinical relationships among conditions. This cross-sectional study included approximately 950,000 Million Veteran Program participants with ≥2 visits. AC and MC phenotypes for 17 conditions spanning COPCs, INT, and OUD were compared in prevalence, case characteristics, comorbidity, and latent structure. Random-thinning analysis compared AC-MC differences to case reduction alone. Construct validity was evaluated through correspondence with expected patterns of association and latent organization. Back pain (AC=58.1%; MC=48.1%), major depressive disorder (41.5%; 36.2%), and post-traumatic stress disorder (32.6%; 29.1%) were most prevalent. MC excluded 33.5% of AC cases on average, and MC cases had greater healthcare utilization, diagnostic burden, opioid exposure, and psychiatric medication use than AC-only cases. The observed mean absolute correlation change (mean |Δr|=0.014) was smaller than in all 1000 random-thinning replicates. Both strategies supported a correlated, four-factor model consistent with "Anxious Misery," "Fear," "Diffuse Pain," and "Head Pain" (AC: CFI=0.987, RMSEA=0.015; MC: CFI=0.987, RMSEA=0.014). The MC strategy reduced prevalence and altered case composition but maintained the expected comorbidity and latent organization patterns among conditions. Findings provide evidence of phenotype construct validity and inform selection of EHR phenotyping strategies for epidemiological and genomic research. PERSPECTIVE: Commonly used EHR phenotyping strategies tested in nearly one million Veterans produce broadly similar latent organization across comorbid and prevalent chronic overlapping pain conditions, internalizing disorders, and opioid use disorder. Findings support construct validity and clarify trade-offs involving case inclusion, recorded burden, and healthcare observation in large-scale research.

Chronic overlapping pain conditions↗
PubMed2026

Comparative Genome-Wide Association Studies of Metabolites and Grain-Related Traits in Common Wheat.

The metabolome is highly diverse and the closest layer to phenotype; therefore, it is commonly regarded as a bridge between the genome and phenome in plants. Here, we performed large-scale metabolome analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and 33 grain-related traits in a diverse panel of natural accessions and a recombinant inbred line (RIL) population. We identified a new network of 2286 associations between 947 metabolites and 33 grain-related traits. Systematic integration of metabolic genome-wide association study (mGWAS) and metabolic quantitative trait locus (mQTL) analyses identified 33 566 significant single-nucleotide polymorphisms (SNPs) and 3128 mQTL. Thirteen annotated metabolites co-localized within a physical interval on 7A. Integration of metabolite-based and phenotype-based GWAS and QTL revealed an overlapped region for gibberellin A4 (GA4) content and grain roundness on 4A. Phenotyping of an ethyl methanesulfonate (EMS)-induced mutant confirmed the role of TaSDR in regulating GA4 content and grain morphology. These findings provide novel insights into the metabolic pathways influencing key grain-related traits and advance our understanding of the complex molecular mechanisms regulating grain metabolites and phenotypes in wheat. The identified metabolic markers and candidate genes provide valuable targets for molecular breeding programs aimed at improving wheat yield and quality.

QTL↗
PubMed1978

Use of a programmable calculator in processing and interpreting serum cholinesterase phenotypes.

Cholinesterase phenotyping is done at 25 degrees C with use of benzoylcholine as substrate and dibucaine, fluoride, chloride, and succinyldicholine as inhibitors. We wrote a diagnostic program in modified BASIC language for the processing and interpretation of these cholinesterase phenotypes. We used the HP 9830A calculator. The diagnostic aspect of the program uses 646 words, a further 86 words being used to run this program. The traditional and the programmed reporting procedures were duplicated for 296 consecutive patients, with no case of disagreement between the two reporting methods as to the appropriate phenotype. The programmed system requested nine repeat analyses more than did the traditional method. Seven of these were due to the tight limits set in the program for the fluoride inhibitor numbers. These tight limits were set to ensure that there was as limited an overlap as possible between the phenotypes E1uE1u and E1uE1f. The remaining two repeats were due to the restrictions placed on the succinyldicholine inhibitor numbers that would be acceptable before a patient was designated as having the relatively rare phenotype, E1aE1f.

Cholinesterases↗
PubMed2025

Dissecting the shared genetic architecture of schizophrenia with ventricular subregion volumes.

Schizophrenia is characterized by cerebral ventricular enlargement as an early and consistent structural anomaly. While genetic factors significantly influence both schizophrenia and cerebral ventricular enlargement, the shared genetic etiology between them requires further investigation. Using summary statistics from recent large genome-wide association studies on schizophrenia and 9 ventricular subregion volumes phenotypes. Gaussian causal mixture modeling was applied to characterize the genetic architecture and overlap between schizophrenia and ventricular subregion volumes phenotypes. Local genetic correlation was investigated with Local Analysis of Variant Association. The conjunctional false discovery rate framework was used to identify the specific shared genetic loci, annotated with FUMA. Gaussian causal mixture modeling estimated schizophrenia to be more polygenic more polygenic (9574 trait-influencing variants) than ventricular subregion volumes phenotypes (157-1267 trait-influencing variants). Conjunctional false discovery rate analysis identified 42 shared genetic loci, 17 loci were identified as novel for both schizophrenia and the ventricular subregion volumes phenotypes. Local Analysis of Variant Association revealed that 11 distinct loci demonstrated significant differences, among which 4 loci were situated in the Major Histocompatibility Complex region. Annotated genes in shared loci were enriched in molecular signaling pathways involved in inflammation and the brain structure. The shared loci between them were annotated and enriched in Major Histocompatibility Complex and inflammation-related pathways, highlighting new opportunities for future investigation.

Schizophrenia↗
PubMed2026

A genome-wide investigation of depression among individuals with and without irritability.

Individuals presenting with both depression and irritability may constitute a different group of individuals with respect to those presenting without irritability, but their biological differences remain unknown. We aimed to identify genetic variants associated with depression among individuals with and without irritability, highlight biological pathways, and test for genetic associations with other traits. We conducted a genome-wide association study (GWAS) using data from the UK Biobank (N&#x2009;=&#x2009;487,409). We identified a group of individuals presenting with depression and reporting never having experienced irritability (depression without irritability, n&#x2009;=&#x2009;35,857, 11.8%), and another with depression and reporting having experienced irritability (depression with irritability, n&#x2009;=&#x2009;23,613, 8.1%) and compared them to controls with no depression or irritability (n&#x2009;=&#x2009;268,012). The GWAS of depression without irritability identified 2 SNPs which reached genome-wide significance (P&#x2009;<&#x2009;5&#xd7;10-8; rs72795440 and rs1233494). The GWAS of depression with irritability (NGWAS&#x2009;=&#x2009;292,485) identified 3 SNPs reaching genome-wide significance (rs2815748, rs102275, and rs7227069). When comparing SNPs between depression phenotypes, 15 SNPs had significantly different effect sizes. Patterns of genetic correlation with 44 complex traits were overall similar between the 2 depression phenotypes, with the highest genetic overlap observed with anxiety for depression without irritability (rg&#x2009;=&#x2009;.77) and neuroticism for depression with irritability (rg&#x2009;=&#x2009;.76). This study shed light into common and distinct biological factors characterizing depression among individuals with and without irritability and contribute to better understanding the genetic architecture of depression to potentially inform treatment and personalized medicine.

Humans↗
PubMed1978

Restoration of growth control in malignantly transformed mouse fibroblasts grown in a chemically defined medium.

The expression of growth control and morphological transformation was studied in methylcholanthrene-transformed C3H/10T 1/2 CL8 cells serially propagated in CDM by first exposing cells to albumin (0.1%) before dispersing them with trypsin (50 microgram/ml). In serum-supplemented media, methylcholanthrene-transformed C3H/10T 1/2 CL8 cells exhibit various aspects of the transformed phenotype such as irregular morphology, extensive cell overlap, lack of density-dependent inhibition of division, a saturation density of 1.1 X 10(5) cells/sq cm and tumorigenicity in vivo. Cell phenotype in CDM was dramatically altered. Methylcholanthrene-transformed C3H/10T 1/2 1/2 CL8 cells adapted to CDM exhibited a regular epithelioid morphology with no cell overlap and formed confluent monolayers of nonproliferating cells at a saturation density of 5 X 10(4) cells/sq cm. The mean generation time of logarithmic-phase cells was 25 to 27 hr. Reversion to the transformed phenotype followed addition of albumin (0.1%) or serum (2%) to logarithmic-phase cultures or exposure (30 to 60 sec) to trypsin (10 microgram/ml). Cultures in CDM reexposed to serum remained highly tumorigenic in vivo. The data suggest that absorbed proteins may block transformation-sensitive cell surface sites responsible for growth control and that these sites are inactivated by trypsin.

Albumins↗
PubMed2026

Understanding tumor adaptations and resistance to MET inhibitors in MET-altered non-small cell lung cancer.

AIM: Type Ib MET inhibitors are clinically active in selected MET-altered non-small cell lung cancer, particularly tumors with MET exon 14 skipping or MET amplification, but acquired resistance remains incompletely understood. Here, we investigated resistance across biologically distinct MET-altered contexts, including MET exon 14 skipping, MET amplification, and MET overexpression. METHODS: Paired baseline and progression samples from seven patients treated with tepotinib or capmatinib were analyzed using spatial transcriptomics, whole-exome sequencing, RNA sequencing, CRISPR screening, and drug-combination assays. Patient-derived cultures and resistant cell-line models were used to explore resistance-associated changes. RESULTS: MET inhibitor resistance was heterogeneous, with persistence of the initial MET alteration in most evaluable cases and emergence of patient-specific genomic events. Three main resistance-associated, often overlapping, routes were identified: on-target MET evolution through kinase-domain alterations; extracellular matrix and tumor-microenvironment remodeling, including collagen and fibronectin upregulation, complement-related signaling, and partial EMT-associated programs; and bypass signaling involving EGFR/HER, MAPK, and PI3K/Akt pathways. In vitro models reproduced several tumor-cell-intrinsic features but only partially captured microenvironment-associated changes. CONCLUSIONS: MET inhibitor resistance in this cohort involved overlapping, context-dependent genomic, phenotypic, and signaling adaptations, supporting combination strategies for MET-altered lung cancer.

CRISPR screen↗
PubMed2025

The DND1-NANOS3 complex shapes the primordial germ cell transcriptome via a heptanucleotide sequence in mRNA 3' UTRs.

The RNA-binding proteins DND1 and NANOS3 are essential for primordial germ cell survival1-5. Their co-immunoprecipitation and overlapping loss-of-function phenotypes suggest joint function6-8, yet how they co-regulate target mRNAs remains unclear. Here, we developed Tandem PAR-CLIP and identified a DND1-NANOS3 ribonucleoprotein that specifically recognizes an AUGAAUU heptanucleotide on target mRNAs, termed the NANOS3-dependent DND1 Recognition Element (N3-DRE). mRNAs containing 3'-UTR N3-DREs are aberrantly upregulated in DND1- or NANOS3-deficient germ cells and encode key cell-cycle and epigenome regulators, such as CDK1. Genome editing showed that the N3-DRE is essential for Cdk1 repression in mouse PGCs in vivo. A 1.7-&#xc5; crystal structure of the ternary complex of DND1, NANOS3, and CDK1-N3-DRE RNA revealed a continuous RNA-binding surface that confers high-affinity, sequence-specific recognition. Together, these findings define the molecular and functional basis of N3-DRE-mediated mRNA regulation in germ cell development. Moreover, we provide a paradigm of two RNA-binding proteins with low (DND1) or no (NANOS3) intrinsic sequence-specificity, jointly building a high-information-content RNA sequence motif that is different from the sum of their individual preferences. Because RNA-binding protein specificities are typically studied individually9-13, rather than in the context of ribonucleoproteins, this type of "two-factor authorization" may be an underappreciated mechanism to protect posttranscriptional gene regulatory networks from aberrant expression of an individual ribonucleoprotein component.

Journal Article↗
PubMed2026

Integration of Morphological and Genome-Wide SNP Data Reveals Regional Diversity in Thai Swamp Buffalo.

Thai swamp buffalo (Bubalus bubalis) are valuable animal genetic resources, but their regional diversity remains incompletely characterized. Morphological records were obtained from 799 buffaloes, and 474 individuals were genotyped using the 90K Axiom&#xae; Buffalo SNP Genotyping Array (Thermo Fisher Scientific, Applied Biosystems&#x2122;, Santa Clara, CA, USA). Qualitative traits included coat color, horn shape, chevron pattern, and hair-whorl distribution, while quantitative characterization covered 30 body measurements. After excluding missing traits, 30 traits adjusted for sex, age, province, and farm from 768 animals were used for morphology-based analyses, which identified regional phenotypic differences but also substantial overlap, consistent with the influence of feeding, management, environment, and local selection on body conformation. Genome-wide SNP analyses indicated a broadly shared genetic background with detectable regional structure, and runs of homozygosity revealed regional differences in genomic autozygosity. The Lower South showed a comparatively strong recurrent-ROH pattern, whereas inference for the Upper South requires caution because of its small genomic sample. Overall, integrating morphology and genome-wide SNP data improves regional characterization, but data-dependent statistics, population-structure estimates, and conservation implications should be interpreted while regarding small sampling and unbalanced data.

Bubalus bubalis↗
PubMed2026

Blood-based proteomic profiling reveals context-dependent changes in BCL2-associated signaling during taxane therapy in breast cancer patients.

The quality of life for many cancer survivors is compromised due to severe, long-lasting side effects of chemotherapy. As part of a pilot, prospective, non-interventional study to examine the side effects of chemotherapy in breast cancer patients, we examined the change in protein expression in blood collected from patients before and after treatment with taxanes for 12&#x2009;weeks. Protein expression was measured with reverse phase proteomic arrays (RPPA), which revealed divergent changes in apoptosis, senescence, and calcium signaling-related proteins depending on treatment setting (neoadjuvant vs. adjuvant). The largest change identified was BCL2 (B-cell lymphoma 2), a founding member of the BCL2 family of proteins that regulate apoptosis. Other proteins regulated by BCL2, including RB1 (retinoblastoma protein 1) and NLRP3 (NLR family pyrin domain containing 3) changed significantly over the course of treatment. These differences are consistent with intracellular calcium signaling dysregulation and activation of stress-response pathways that overlap with senescent-associated secretory phenotype (SASP)-like signaling, which has been implicated in cancer recurrence. To contextualize these observations, we generated Kaplan-Meier survival curves using publicly available proteomics data from The Cancer Proteome Atlas (TCPA). This work aims to demonstrate how blood-based proteomics can serve as a non-invasive method to monitor systemic physiological shifts during cancer therapy, offering a framework for generating hypotheses about chemotherapy timing and long-term outcomes.

Humans↗
PubMed2026

Hepatic metabolic adaptation to endurance exercise: temporal and sex differences by multiomics integration and validation.

BACKGROUND: Although endurance exercise benefits liver health, sex-specific adaptive trajectories remain unclear. This study mapped dynamic liver adaptation in males and females during prolonged training and identified underlying molecular programs. METHODS: Using publicly available time-resolved liver multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we established a computational pipeline for differential analysis of transcriptomic, proteomic, phosphoproteomic, and metabolomic data with FDR correction, followed by FGSEA pathway enrichment. Kinase activities were inferred through ortholog mapping and PhosphoSitePlus. Cross-omics co-expression networks were constructed using WGCNA and topological overlap to link omics features with physiological phenotypes. For experimental validation, liver tissues were collected from endurance-trained Sprague-Dawley rats, and key nodes were confirmed by Western blotting, qRT-PCR, and immunofluorescence/immunohistochemical staining. Public scRNA-seq data were further integrated to map multi-omics signals to single-cell resolution and assess functional changes in specific cell types. RESULTS: The hepatic response to exercise stress was stage-specific, shifting from early transcriptional activation to later proteomic and metabolic remodeling. Multi-omics integration revealed distinct sex-associated adaptive trajectories: males were more strongly associated with energy metabolism, redox-related programs, and amino acid/organic acid catabolism, whereas females showed prominent membrane lipid remodeling, proteostasis -related programs, and mitochondrial/ribosomal translational features. Single-cell analysis showed that tissue remodeling occurred without major lineage turnover, instead involving altered communication among pre-existing cell communities. Validation of PPP1R3G identified a protein-dominant exercise-responsive marker, supporting the contribution of post-transcriptional or protein-level regulation. CONCLUSIONS: Hepatic adaptation to endurance stress follows a cross-omics evolutionary pattern with sex-specific reprogramming of energy supply and homeostatic maintenance. This time-resolved framework clarifies how exercise improves liver function and supports sex-oriented metabolic interventions and therapeutic target discovery.

Animals↗
PubMed2026

IgA Vasculitis with necrotizing arteritis: a multicenter retrospective study from the French Vasculitis Study Group and systematic review of the literature.

IgA vasculitis (IgAV) primarily affects small vessels, but rare cases with necrotizing arteritis (NA) raise questions about overlap with polyarteritis nodosa (PAN). To characterize IgAV with necrotizing arteritis (IgAV-NA) and compare its phenotype with classical IgAV and PAN. We performed a multicenter retrospective study combined with a systematic literature review (1990-2025). Patients fulfilled EULAR/PRINTO/PRES IgAV criteria, had pathological or imaging evidence of NA in small or medium arteries, and were ANCA-negative. Thirty patients were included (7 from databases, 23 from the literature). NA was confirmed by biopsy (n&#x2009;=&#x2009;16) or vascular imaging (n&#x2009;=&#x2009;14). Clinical features, treatments, remission, and mortality were compared with 257 adult IgAV and 196 PAN patients. Median age was 54.5 years. IgAV-NA was characterized by severe manifestations, including gastrointestinal bleeding, perforation, surgical abdomen, neuropathy, pancreatitis, and livedo. Compared with classical IgAV, IgAV-NA showed significantly higher rates of multi-organ involvement and mortality. Compared with PAN, IgAV-NA shared vascular complications but had less fever and neuropathy. Despite arterial involvement, patients did not fulfil PAN criteria. IgAV-NA represents a rare, severe IgAV phenotype with life-threatening complications rather than an IgAV-PAN overlap. Severe or atypical IgAV presentations should prompt vascular imaging and intensified immunosuppression.

Humans↗
PubMed2026

The long road to diagnosis: recessive PMPCB deficiency hidden behind a dominant familial VCP defect.

Multiple mitochondrial dysfunctions syndrome 6 (MMDS6), caused by biallelic likely pathogenic variants in PMPCB, is an extremely rare autosomal recessive childhood-onset neurodegenerative disorder, with only six reported cases to date, most resulting in early mortality. Pathogenic variants in VCP cause multisystem proteinopathy 1 (MSP1), an autosomal dominant adult-onset disorder encompassing inclusion body myopathy (IBM), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), typically presenting in mid-adulthood. We describe a 23-year-old female with two likely pathogenic variants presumed to be in trans in PMPCB and a co-occurring pathogenic VCP variant. She was misdiagnosed for over 20&#xa0;years with early-onset VCP-related neurodegeneration due to a maternal family history of ALS. Her disease began at birth with microcephaly and progressed throughout childhood, including developmental regression, cerebellar and cerebral atrophy, optic atrophy, seizures, spasticity, dysarthria, and loss of ambulation. Initial genetic testing identified only the familial VCP variant. Updated genomic sequencing at age 23 revealed two likely pathogenic PMPCB variants, strong supporting a diagnosis of MMDS6. Her clinical features closely align with previously reported MMDS6 cases and are inconsistent with the typical adult-onset phenotype of VCP-associated disorders. While she shares overlapping features with VCP-related disease (limb-girdle weakness, spasticity, FTD), the timing and severity of her neurodevelopmental findings support MMDS6 as the primary diagnosis. Early mitochondrial dysfunction may predispose her to an accelerated or more severe future VCP-associated phenotype. This is the first report of combined likely pathogenic and pathogenic variants in PMPCB and VCP respectively, expanding the phenotypic spectrum of both disorders. The case underscores the necessity of periodic re-evaluation with advanced genetic testing, highlights important ethical and familial implications, and informs future diagnosis and management of patients with overlapping rare genetic conditions.

Dual molecular diagnosis↗
PubMed2024

Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo.

Proteins carrying a signal peptide and/or a transmembrane domain enter the intracellular secretory pathway at the endoplasmic reticulum (ER) and are transported to the Golgi apparatus via COPII vesicles or tubules. SAR1 initiates COPII coat assembly by recruiting other coat proteins to the ER membrane. Mammalian genomes encode two SAR1 paralogs, SAR1A and SAR1B. While these paralogs exhibit ~90% amino acid sequence identity, it is unknown whether they perform distinct or overlapping functions in vivo. We now report that genetic inactivation of Sar1a in mice results in lethality during midembryogenesis. We also confirm previous reports that complete deficiency of murine Sar1b results in perinatal lethality. In contrast, we demonstrate that deletion of Sar1b restricted to hepatocytes is compatible with survival, though resulting in hypocholesterolemia that can be rescued by adenovirus-mediated overexpression of either SAR1A or SAR1B. To further examine the in vivo function of these two paralogs, we genetically engineered mice with the Sar1a coding sequence replacing that of Sar1b at the endogenous Sar1b locus. Mice homozygous for this allele survive to adulthood and are phenotypically normal, demonstrating complete or near-complete overlap in function between the two SAR1 protein paralogs in mice. These data also suggest upregulation of SAR1A gene expression as a potential approach for the treatment of SAR1B deficiency (chylomicron retention disease) in humans.

Animals↗
PubMed2024

Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo.

Proteins carrying a signal peptide and/or a transmembrane domain enter the intracellular secretory pathway at the endoplasmic reticulum (ER) and are transported to the Golgi apparatus via COPII vesicles or tubules. SAR1 initiates COPII coat assembly by recruiting other coat proteins to the ER membrane. Mammalian genomes encode two SAR1 paralogs, SAR1A and SAR1B. While these paralogs exhibit ~90% amino acid sequence identity, it is unknown whether they perform distinct or overlapping functions in vivo. We now report that genetic inactivation of Sar1a in mice results in lethality during mid-embryogenesis. We also confirm previous reports that complete deficiency of murine Sar1b results in perinatal lethality. In contrast, we demonstrate that deletion of Sar1b restricted to hepatocytes is compatible with survival, though resulting in hypocholesterolemia that can be rescued by adenovirus-mediated overexpression of either SAR1A or SAR1B. To further examine the in vivo function of these 2 paralogs, we genetically engineered mice with the Sar1a coding sequence replacing that of Sar1b at the endogenous Sar1b locus. Mice homozygous for this allele survive to adulthood and are phenotypically normal, demonstrating complete or near-complete overlap in function between the two SAR1 protein paralogs in mice. These data also suggest upregulation of SAR1A gene expression as a potential approach for the treatment of SAR1B deficiency (chylomicron retention disease) in humans.

Preprint↗