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PubMed2026

The Clinical Application of Refined Risk Estimates Study in BRCA1 and BRCA2 Pathogenic Variant Carriers: A Randomized Controlled Trial.

UNLABELLED: Individuals with germline BRCA1 or BRCA2 pathogenic variants (PV) may struggle with risk management decision-making. Advancements in technology could provide more specific risk information to patients, but the impact of this information is unknown. The Clinical Application of Refined Risk Estimates Study is a two-arm randomized controlled trial in women with a BRCA1/BRCA2 PV. The primary objective was to determine whether genotype-informed personalized cancer risk estimates (GRE) compared with standard lifetime cancer risk estimates (SRE) decreased decisional conflict related to cancer risk management decision-making. Women were recruited following the disclosure of their PV results. Participants completed a baseline survey and were randomized 1:1 to receive a GRE or SRE. After receiving their results, participants completed a follow-up survey. Likert and continuous data measures were analyzed using linear regression. There were no differences in decisional conflict between study arms at follow-up. However, individuals in the SRE arm showed an increased need for personal structure compared with those in the GRE arm (P = 0.02). Compared with baseline, individuals within the SRE arm showed decreased decisional conflict (P = 0.003) and increased perceived stress (P = 0.02) at follow-up. A more personalized cancer risk estimate did not decrease decisional conflict in women with BRCA1/BRCA2 PVs. Future studies will determine whether a GRE affects actual decision-making behaviors. PREVENTION RELEVANCE: Women with a germline PV in BRCA1 or BRCA2 have significantly elevated risks of developing breast and ovarian cancers. This randomized controlled trial evaluates the impact of polygenic risk scores on decisional conflict related to breast and ovarian cancer prevention and risk management in those with BRCA1/BRCA2 PVs.

Humans↗
PubMed2006

Subthreshold and superthreshold coexistence of pathogen variants: the impact of host age-structure.

It is well known that in the most general epidemic models with multiple pathogen variants a competitive exclusion principle is valid, such that the variant with the highest reproduction number eliminates the rest. Mechanisms such as super-infection, coinfection, and cross-immunity can lead to pathogen polymorphism where multiple strains coexist. It is also known that variability of infectivity with host age can destabilize the endemic equilibrium and cause oscillations. In this article we show that the hosts' chronological age can itself lead to coexistence of microparasites in the most basic model where competitive exclusion will occur without the age structure. Moreover, the host age-structure leads to multiple subthreshold dominance equilibria, and both weakly and strongly subthreshold coexistence. We find that the two pathogens cannot cooperate to persist subthreshold if neither one of them can persist subthreshold by itself. If, however, one of them can persist subthreshold by itself, it can cause the two pathogens to coexist in a strongly subthreshold equilibrium. The second strain that persists subthreshold through the mediation of the first always has a lower virulence. Our results show that age structure in infectivity can permit the coexistence of competing pathogens when the incidence is of proportionate mixing type (frequency-dependent transmission) and at least one of the strains is virulent.

Age Factors↗
PubMed2026

The bioinformatics approach to identifying pathogenic variants for colorectal cancer (CRC).

Colorectal cancer (CRC) is the third most prevalent cancer globally, accounting for 9.6% of newly diagnosed cases and 9.3% of cancer-related deaths. It develops from the uncontrolled proliferation of glandular cells in the colon and rectum and is categorized into three primary types: sporadic, hereditary, and colitis-associated. While genetic susceptibility is a key factor in CRC pathogenesis, identifying high-impact pathogenic variants remains a significant challenge. This study integrates bioinformatics and population genetics approaches to identify CRC-associated single-nucleotide polymorphisms (SNPs) with potential clinical significance. CRC-associated SNPs were extracted from the Genome-Wide Association Studies (GWAS) Catalog, functionally annotated via HaploReg, and validated via Ensembl. In addition, expression quantitative trait locus (eQTL) data from the GTEx database were used to assess the effects of these variants on gene expression across human tissues. Our analysis identified three high-priority SNPs (rs9379084, rs3184504, and rs11557154) associated with the RREB1, ATXN2, SH2B3, and DCAF12 genes, which exhibited marked allele frequency differences among populations. These findings suggest potential biomarkers for CRC risk assessment and highlight the importance of genetic screening across diverse populations.

Bioinformatics↗
PubMed2026

Risks of non-breast, non-ovarian cancers for BRCA1 and BRCA2 pathogenic variant carriers: a prospective cohort study.

BACKGROUND: The non-breast non-ovarian cancers associated with BRCA1 and BRCA2 pathogenic variants (PVs) are controversial. We aimed to examine this using a prospective cohort design. METHODS: This study included 1260 BRCA1 and 1058 BRCA2 PV carriers (91% were females) from two consortia: the Breast Cancer Family Registry (BCFR) and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer Follow-Up Study (kConFab-FUS). The carriers were free of cancer other than breast or ovarian cancer at baseline and had a median baseline age of 45.5 years. For 16 types of non-breast, non-ovarian cancers, standardized incidence ratios (SIRs) relative to population incidence, the probabilities of relative risk effect size > 2 (i.e., moderate risk) and cumulative risks to age 80 years were estimated. RESULTS: During a median follow-up time of 11.4 years, 161 non-breast, non-ovarian cancers were observed. For BRCA1 PV carriers, little evidence of increased risk was observed. The prostate, pancreatic, and all non-pancreatic cancer SIRs were 1.7 (95% CI 0.7-4.2), 1.1 (95% CI 0.3-4.6) and 0.85 (95% CI 0.68-1.06), respectively; the probabilities of relative risk > 2 were 0 and 67% for prostate and pancreatic cancers, respectively. For BRCA2 PV carriers, increased risks of pancreatic (SIR = 6.6, 95% CI 3.8-11.6), prostate (SIR = 3.6, 95% CI 1.9-6.8) and stomach (SIR = 3.1, 95% CI 1.01-9.8) cancer were observed, with a cumulative risk to age 80 years of 8.3, 82.0, and 1.6%, respectively. For all the other non-breast, non-ovarian cancers combined, the SIR was 0.85 (95% CI 0.66-1.10). CONCLUSIONS: Apart from pancreatic, prostate, and possibly stomach cancers for BRCA2 PV carriers, and possibly pancreatic cancer for BRCA1 PV carriers, there is no evidence that BRCA1 and BRCA2 PV carriers have substantially increased risks of other non-breast, non-ovarian cancers. Our prospective risk estimates are informative for cancer risk assessment for people with BRCA1 and BRCA2 PVs.

Humans↗
PubMed1998

A spontaneous low-pathogenic variant of Theiler's virus contains an amino acid substitution within the predominant VP1(233-250) T-cell epitope.

Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelination after intracerebral inoculation of the virus into susceptible mouse strains. We isolated from a TMEV BeAn 8386 viral stock, a low-pathogenic variant which requires greater than a 10,000-fold increase in viral inoculation for the manifestation of detectable clinical signs. Intracerebral inoculation of this variant virus induced a strong, long-lasting, protective immunity from the demyelinating disease caused by pathogenic TMEV. The levels of antibodies to the whole virus as well as to the major linear epitopes were similar in mice infected with either the variant or wild-type virus. However, persistence of the variant virus in the central nervous system (CNS) of mice was significantly lower than that of the pathogenic virus. In addition, the T-cell response to the predominant VP1 (VP1(233-250)) epitope in mice infected with the variant virus was significantly weaker than that in mice infected with the parent virus, while similar T-cell responses were induced against another predominant epitope (VP2(74-86)). Further analyses indicated that a change of lysine to arginine at position 244 of VP1, which is the only amino acid difference in the P1 region, is responsible for such differential T-cell recognition. Thus, the difference in the T-cell reactivity to this VP1 region as well as the low level of viral persistence in the CNS may account for the low pathogenicity of this spontaneous variant virus.

Amino Acid Substitution↗
PubMed2026

The Same Homozygous Pathogenic Variant in CHAT Underlies Lethal Fetal Akinesia Syndrome in Three Xhosa South African Fetuses.

What is already known about this topic? ◦. Biallelic pathogenic variants in CHAT cause congenital myasthenic syndrome (CMS), typically presenting postnatally with episodic apnea and neuromuscular weakness. CHAT encodes choline acetyltransferase, essential for acetylcholine synthesis at the neuromuscular junction, and previously has not been associated with uniformly lethal prenatal phenotypes. What does this study add? ◦. We demonstrate that biallelic CHAT variants can cause severe fetal akinesia resulting in lethal multiple pterygium syndrome, expanding the phenotypic spectrum to include presentation, lethality and supporting inclusion of CHAT in fetal akinesia gene panels.

CHAT↗
PubMed2024

Novel pathogenic variant in a mild case of type B molybdenum cofactor deficiency: case report and literature review.

BACKGROUND: Molybdenum cofactor deficiency (MoCD) is a rare metabolic disorder caused by pathogenic variants in the highly conserved biosynthetic pathway of molybdenum cofactor (MoCo), resulting in sulfite intoxication. MoCD may present in a clinically severe, fatal form marked by intractable seizures after birth, hyperekplexia, microcephaly and cerebral atrophy, or a later onset form with a more varied clinical course. Three types of MoCD have been described based on the effected gene along the MoCo synthesis pathway: type A (MOCS1); type B (MOCS2 or MOCS3) and type C (GPHN). The MOCS2 gene is bicistronic, encoding the small (MOCS2A) and large (MOCS2B) subunits with an overlapping coding region. This case report describes a patient with the first known variant causative of mild disease in the overlapping bicistronic region (c.263 G > C) and the first ever described in the highly conserved C-terminal glycine-glycine motif of MOCS2A. CASE PRESENTATION: The patient developed normally until age 12 months when she presented in the setting of acute illness with developmental regression, low serum uric acid, and MRI with bilateral globus pallidus (GP) injury. Exome sequencing identified a homozygous variant of unknown significance in the MOCS2 gene and the diagnosis of MoCD type B was confirmed by the patient's low serum uric acid coupled with elevated urine sulfocysteine and associated metabolites, resulting in gene reclassification. Nearly four years after her initial presentation she has demonstrated progress in language and motor domains, consistent with a mild phenotype of MoCD. CONCLUSIONS: The case emphasizes challenges in identifying atypical forms of rare diseases, the importance of exome sequencing to identify mild cases of MoCD, and the ongoing challenges with understanding the MOCS2 gene. While one FDA approved treatment exists for MoCD type A, further research into the mechanisms of phenotype-genotype differences among this patient population may aid in additional therapeutic options for MoCD.

Female↗
PubMed2026

Generation of an induced pluripotent stem cell line, LGMi002-A, from a Bardet-Biedl Syndrome patient with a BBS5 homozygous pathogenic variant.

The human induced pluripotent stem cell (iPSC) line, iPSC-BBS5stbg1, derived from a patient with a Bardet-Biedl Syndrome (BBS) phenotype and carrying a BBS5 homozygous pathogenic variant: c.123delA, p.Gly42Glufs*11 is described. The reprogramming of the patient's dermal fibroblasts was achieved using the non-integrative Sendai virus system delivering the OCT4, SOX2, KLF4 and c-MYC (OSKM) transcription factors. The established iPSC line iPSC-BBS5stbg1 displays typical iPSC morphology, maintains genomic stability, and demonstrates the ability to differentiate into cell types representative of the three embryonic germ layers. This iPSC line constitutes robust and relevant cellular model for studying BBS-associated disease mechanisms and ciliary dysfunction.

Humans↗
PubMed1983

Genetic variability of herpes simplex virus: development of a pathogenic variant during passaging of a nonpathogenic herpes simplex virus type 1 virus strain in mouse brain.

Herpes simplex virus type 1 ANG (HSV-1 ANG) is originally nonpathogenic for inbred mice upon intraperitoneal intravenous, or intravaginal inoculation. In contrast, mice died of encephalitis within 4 to 5 days after intracerebral inoculation with this strain. HSV-1 ANG was serially passaged in mouse brains. In two independent series, peripherally pathogenic virus variants had developed and accumulated in the virus progeny after 12 to 15 intracerebral passages. In mixed infections both nonpathogenic and pathogenic viruses replicated at the primary site of infection and spread to various organs. However, only the pathogenic phenotype could be recovered from the spinal cord and the brain. Comparison of the restriction enzyme cleavage patterns of pathogenic ANG and nonpathogenic ANG virus DNAs revealed distinct alterations in the S-segment (US) sequences bounded by coordinates 0.953 and 0.958 in the prototype orientation and by coordinates 0.862 to 0.867 in the IS orientation of the viral genome. However, it is not known whether these alterations are physiologically relevant to the observed changes in pathogenicity. When coinjected intraperitoneally at 50 to 100-fold excess, the nonpathogenic HSV-1 ANG protected mice against its own pathogenic variant as well as against other pathogenic HSV-1 strains. Pathogenic HSV-1 ANG proved to be genetically and phenotypically stable for at least 25 serial passages in tissue culture at either high or low multiplicity of infection.

Animals↗
PubMed2026

Impact of BRCA2 pathogenic variants on outcomes to first-line CDK4/6 inhibitors plus endocrine therapy in HR-positive/HER2-negative metastatic breast cancer.

BACKGROUND: Currently, three cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are approved in combination with endocrine therapy (ET) as first-line treatment of patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). The impact of homologous recombination repair (HRR) pathogenic variants (PV) on outcomes with first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC remains uncertain. PATIENTS AND METHODS: We conducted a multicenter, real-world, case-control study including 233 patients with HR-positive/HER2-negative MBC treated with first-line CDK4/6i and ET. Among them, 116 presented HRR PVs and 117 were matched controls with negative germline testing. The primary objective was to compare progression-free survival (PFS) and overall survival among germline-BRCA2 PV carriers, other HRR PV carriers, and controls. To minimize baseline differences in prognostic factors between PV carriers and controls, inverse probability of treatment weighting was applied. Molecular analyses in pre-CDK4/6i samples among patients with BRCA2 PV were carried out, including RAD51-foci, PAM50 intrinsic subtype, and RB1 loss of heterozygosity (LOH). RESULTS: Among the included 233 patients, median age at diagnosis was 45 years (interquartile range 39-56) and 33% had de novo metastatic disease. Primary resistance to adjuvant ET was present in 10% and secondary resistance in 27%. After a median follow-up of 44 months, patients with germline-BRCA2 PVs (n = 67) had significantly shorter PFS [11 versus 27 months; adjusted hazard ratio (aHR) 2.73, 95% confidence interval (CI) 1.65-4.51, P < 0.001] compared with controls. Among patients with endocrine-sensitive disease, germline BRCA2 PV carriers had markedly shorter PFS (median PFS 12 versus 39 months; aHR 4.04; 95% CI 1.82-8.98, P < 0.001). Exploratory analyses revealed RB1 LOH before CDK4/6i-treatment in most evaluable BRCA2 tumors. CONCLUSIONS: BRCA2 PVs were independently associated with poorer outcomes to first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC compared with controls, especially relevant among patients with endocrine-sensitive disease. These findings suggest that patients with a germline PV in BRCA2 may require alternative first-line strategies.

Humans↗
PubMed2026

Risk of desmoid tumor based on APC pathogenic variant location and surgical history in familial adenomatous polyposis: a U.S. community cohort study.

Desmoid tumors (DT) are a leading cause of morbidity and mortality in patients with familial adenomatous polyposis (FAP), yet available data on DT risk remain limited and have been largely derived from large registries or tertiary referral centers. Risk in community-based U.S. populations is poorly defined, which hinders presurgical counseling. We conducted a retrospective cohort study of patients with pathogenic or likely pathogenic variants (PV/LPV) in APC identified through the Kaiser Permanente Northern California Electronic Database, a community-based system serving 4.6&#xa0;million members. We evaluated the association of APC PV/LPV location and prior abdominal surgery with DT risk using multivariable logistic regression, adjusting for sex, race and ethnicity, and family history. Among 328 patients with FAP, 36 (11.0%) developed DT. DT risk was highest when the APC variant was centrally located (codon 600-1600). Family history was independently associated with increased risk (adjusted odds ratio [aOR] 4.34; 95% confidence interval [CI] 1.12-16.86). All colorectal surgeries were associated with a significantly elevated DT risk: ileostomy (aOR 12.07; 2.10-69.47), subtotal colectomy with ileorectal anastomosis (aOR 9.03; 1.63-49.96), and total proctocolectomy with ileal pouch-anal anastomosis (aOR 10.98; 2.12-56.81). In contrast, non-colorectal surgery was not associated with increased risk (aOR 0.73). In this large community-based U.S. cohort, central APC variant location, family history, and colorectal surgery were associated with increased DT risk. Our findings extend the current literature on DT risk in FAP and help refine presurgical risk-stratification and counseling for these patients.

Humans↗
PubMed2004

Intrinsic versus mutation dependent instability/flexibility: a comparative analysis of the structure and dynamics of wild-type transthyretin and its pathogenic variants.

Transthyretin (TTR) is one of the about 20 known human proteins associated with amyloidosis which is characterized by the accumulation of amyloid fibrils in tissues or extracellular matrix surrounding vital organs. Unlike Alzheimer's fibrils that comprise a fragment of a large precursor protein, TTR amyloid fibrils are composed of both full-length protein and fragments of the molecule. The native state of TTR is a homotetramer with eight beta-strands organized into a beta-sandwich in each monomer. To elucidate the structural reorganization mechanisms preceding amyloid formation, it is important to characterize the dynamic features of the wild-type native state as well as to reveal the influence of disease-associated mutations on the structure and dynamics. Molecular dynamics (MD) simulations complement X-ray crystallography and D-H exchange to capture the intrinsically unstable/flexible sites of the wild-type as well as the mutation dependent unstable sites of the pathogenic variants. Our results of MD simulations have shown that the Leu55-->Pro (L55P) mutation occurs in an intrinsically unstable site, leading to substantial local and global structural changes. This observation supports the early speculation that the C-strand-loop-D-strand rearrangement leads to the formation of amyloidogenic intermediates. In addition to the D strand, the alpha-helical region and the strands at the monomer-monomer interface are also intrinsically unstable. The central channel of L55P-TTR undergoes opening and closing fluctuations, which may provide an explanation for the fact that while the mutation is far from the channel, the mutant shows a substantial low binding affinity of thyroxine.

Binding Sites↗
PubMed2024

Identification of a novel EYA4 likely pathogenic variant in a Chinese family with postlingual non-syndromic hearing loss and analysis of molecular epidemiology of EYA4 variants.

BACKGROUND: EYA4 variants are responsible for DFNA10 deafness. Due to its insidious onset and slow progression, hearing loss in autosomal dominant non-syndromic hearing loss (ADNSHL) is usually challenging to detect early in clinical settings, with limited intervention options. Genetic testing can aid in early detection of hearing loss, enabling timely intervention to reduce disability rates and improve the quality of life. METHODS: In this study, we report the case of a Chinese family with postlingual and progressive hearing loss that was passed down for four generations. Whole-exome sequencing (WES) was performed on DNA samples from the proband. Candidate variants identified in the proband and family members were confirmed via Sanger sequencing. In silico prediction tools and co-segregation analyses were used to assess the pathogenicity of identified variants. A literature review of known EYA4 variants was performed, analysing variant frequency, distribution characteristics across different populations, and genotype-phenotype correlations. RESULTS: We identified a novel EYA4 variant, c.1745_1748del (p.Glu582ValfsTer6), in a Chinese family with ADNSHL, and co-segregation with the family's phenotype was confirmed. The audiometry showed mid-to-high frequency downsloping hearing loss. To date, 52 pathogenic variants of EYA4 have been reported, with majority identified in Asian populations. Most observed are the missense and frameshift variants. CONCLUSIONS: A novel variant of EYA4 was identified in a Chinese family with postlingual hearing loss, contributing to the expanding spectrum of EYA4 variants. The audiological features of EYA4 variants are highly heterogeneous and often challenging to detect early in clinical settings. Our findings highlight the significance of genetic testing in patients presenting with postlingual hearing loss.

Humans↗
PubMed2024

WilsonGenAI a deep learning approach to classify pathogenic variants in Wilson Disease.

BACKGROUND: Advances in Next Generation Sequencing have made rapid variant discovery and detection widely accessible. To facilitate a better understanding of the nature of these variants, American College of Medical Genetics and Genomics and the Association of Molecular Pathologists (ACMG-AMP) have issued a set of guidelines for variant classification. However, given the vast number of variants associated with any disorder, it is impossible to manually apply these guidelines to all known variants. Machine learning methodologies offer a rapid way to classify large numbers of variants, as well as variants of uncertain significance as either pathogenic or benign. Here we classify ATP7B genetic variants by employing ML and AI algorithms trained on our well-annotated WilsonGen dataset. METHODS: We have trained and validated two algorithms: TabNet and XGBoost on a high-confidence dataset of manually annotated, ACMG & AMP classified variants of the ATP7B gene associated with Wilson's Disease. RESULTS: Using an independent validation dataset of ACMG & AMP classified variants, as well as a patient set of functionally validated variants, we showed how both algorithms perform and can be used to classify large numbers of variants in clinical as well as research settings. CONCLUSION: We have created a ready to deploy tool, that can classify variants linked with Wilson's disease as pathogenic or benign, which can be utilized by both clinicians and researchers to better understand the disease through the nature of genetic variants associated with it.

Hepatolenticular Degeneration↗
PubMed2025

Extracting and calibrating evidence of variant pathogenicity from population biobank data.

Genomic medicine requires a robust evidence base of variant phenotypic impacts, which remains incomplete even in extensively studied genes with monogenic disease associations. Here, we evaluated the broad potential of using population cohort data to identify evidence that can be used in variant assessment. Across 41 genes related to 18 clinically actionable monogenic phenotypes, we calculated variant-level odds ratios of disease enrichment using data from 469,803 UK Biobank participants. We found significant differences in odds ratio values between ClinVar-labeled pathogenic and benign variants in 11 phenotypes, spanning both common and rare disorders. To facilitate clinical translation, we calibrated the strength of evidence provided by variant-level odds ratios to align with American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) interpretation guidelines (PS4 criterion) and found that odds ratios may reach "moderate," "strong," or "very strong" evidence, varying by phenotype and gene. Overall, we found that 2.6% (N = 12,350) of participants harbor a rare variant of uncertain significance (VUS) with at least moderate evidence of pathogenicity-an indication of potentially unrecognized disease risk. Finally, by incorporating computational and functional data alongside population-based odds ratios, we identified variants that met the criteria for clinical reclassification. Notably, using this approach, we identified that 12.4% of rare VUSs in LDLR seen in participants meet diagnostic criteria to be classified as likely pathogenic, demonstrating its potential to scale the reclassification of VUSs.

Humans↗
PubMed2002

Preferential induction of IL-10 in APC correlates with a switch from Th1 to Th2 response following infection with a low pathogenic variant of Theiler's virus.

Theiler's murine encephalomyelitis virus induces immune-mediated demyelination in susceptible mice after intracerebral inoculation. A naturally occurring, low pathogenic Theiler's murine encephalomyelitis virus variant showed a single amino acid change within a predominant Th epitope from lysine to arginine at position 244 of VP1. This substitution is the only one present in the entire viral capsid proteins. In this paper, we demonstrate that the majority of T cells specific for VP1(233-250) and VP2(74-86) from wild-type virus-infected mice are Th1 type and these VP1-specific cells poorly recognize the variant VP1 epitope (VP1(K244R)) containing the substituted arginine. In contrast, the Th2-type T cell population specific for these epitopes predominates in variant virus-infected mice. Immunization with UV-inactivated virus or VP1 epitope peptides could not duplicate the preferential Th1/Th2 responses following viral infection. Interestingly, the major APC populations, such as dendritic cells and macrophages, produce IL-12 on exposure to the pathogenic wild-type virus, whereas they preferentially produce IL-10 in response to the low pathogenic variant virus. Thus, such a spontaneous mutant virus may have a profoundly different capability to induce Th-type responses via selective production of cytokines involved in T cell differentiation and the consequent pathogenicity of virally induced immune-mediated inflammatory diseases.

Amino Acid Sequence↗
PubMed2026

Large-scale functional annotation establishes a reference framework for human LRRK2 variants.

Pathogenic variants in leucine-rich repeat kinase 2 (LRRK2)1are among the most frequent monogenic causes of Parkinson's disease (PD)2 and act through a gain-of-function mechanism of increased kinase activity. LRRK2-targeted therapies are in clinical development, but interpretation of the rapidly expanding catalogue of rare LRRK2 variants remains a barrier to translation. Here, we present functionally annotated data on >350 LRRK2 coding variants using a standardized cellular assay with Rab10 phosphorylation as a readout of kinase activity and integrated these data with curated genetic and clinical annotations from the Movement Disorders Society Genetic Mutation Database (MDSGene). Variants differed in activation magnitude, ranging from modest increases (e.g., p.G2019S) to strongly activating substitutions such as p.Y1699C or p.L1795F. Activating variants occurred across the full length of LRRK2, although the largest effects clustered within the ROC-COR regulatory hub, where structural analysis identified subdomains forming an allosteric scaffold controlling kinase output. All known/established pathogenic variants showed increased activity, whereas benign and likely benign variants remained within the wild-type range. Functional effect sizes correlated with pathway activation in patient-derived immune cells, altogether providing a framework for ACMG-based variant interpretation in which kinase activation can support PS3 functional evidence for reclassification of variants.

Protein phosphorylation↗
PubMed2006

Local unfolding in a destabilized, pathogenic variant of superoxide dismutase 1 observed with H/D exchange and mass spectrometry.

Hydrogen exchange monitored by mass spectrometry has been used to study the structural behavior of the pathogenic A4V variant of superoxide dismutase 1 (SOD1) in the metal-free (apo) form. Mass spectrometric data revealed that in the disulfide-intact (S-S) form, the A4V variant is destabilized at residues 50-53, in the disulfide subloop of the dimer interface, but many other regions of the A4V protein exhibited hydrogen exchange properties identical to that of the wild type protein. Additionally, mass spectrometry revealed that A4V apoSOD1(S-S) undergoes slow localized unfolding in a large segment of the beta-barrel that included beta3, beta4, and loops II and III. In the disulfide-reduced form, A4V apoSOD1 exchanged like a "random coil" polypeptide at 20 degrees C and began to populate folded states at 4 degrees C. These local and global unfolding events could facilitate intermolecular protein-protein interactions that cause the aggregation or neurotoxicity of A4V SOD1.

Cold Temperature↗