Monogenic Cause Research Articles

Functional insights of an uncommon hypomorphic variant in IL2RG as a monogenic cause of CVID-like disease with antibody deficiency and T CD4 lymphopenia

BackgroundOver the last decade, the identification of hypomorphic variants in patients previously diagnosed with Common Variable Immunodeficiency (CVID) has led to the association of milder phenotypes with variants of the IL2RG gene that are usually related to severe combined immunodeficiency. Indeed, several revertant mosaicisms have been described in cases with hypomorphic variants in that gene. Our main objective herein was the functional characterization of p. (Pro58Thr) variant in the IL2RG gene in an adult patient with antibody deficiency and moderate CD4+ T cell lymphopenia.MethodsEvaluation of the patient included a clinical examination and a complete analysis of the peripheral blood phenotype. To further explore IL2RG functionality we selected downstream signaling readouts, namely STAT3 and STAT5 phosphorylation, NK degranulation and B- and T-cell proliferation capacity in vitro, which can be measured by flow cytometry, that reflect the strength of homeostatic signaling pathways in resting cells and after activation.ResultsThe patient presented reduced CD132 expression and conserved T- and B-cell proliferation capacity in vitro. However, we found that intracellular signaling downstream of IL2γc is affected, with reduced STAT3 phosphorylation after IL-21 stimulation in B cells and CD4 T cells. In addition, CD4+ T cells showed a reduced STAT5 phosphorylation in response to IL-2, which was not so evident in CD8+ T cells. NK degranulation was impaired upon PHA and IL-2 as well as plasmablast differentiation in vitro.ConclusionWe conclude that p. (Pro58Thr) in the IL2RG gene is functionally a hypomorphic variant, as reported previously. Although the functionality of CD8+ is less impaired than the rest of the lymphocyte subsets, we did not detect a reversion of the variant in isolated CD8+, CD4+, CD19+ or NK cells.

Trans-ancestral rare variant association study with machine learning-based phenotyping for metabolic dysfunction-associated steatotic liver disease

BackgroundGenome-wide association studies (GWAS) have identified common variants associated with metabolic dysfunction-associated steatotic liver disease (MASLD). However, rare coding variant studies have been limited by phenotyping challenges and small sample sizes. We test associations of rare and ultra-rare coding variants with proton density fat fraction (PDFF) and MASLD case–control status in 736,010 participants of diverse ancestries from the UK Biobank, All of Us, and BioMe and performed a trans-ancestral meta-analysis. We then developed models to accurately predict PDFF and MASLD status in the UK Biobank and tested associations with these predicted phenotypes to increase statistical power.ResultsThe trans-ancestral meta-analysis with PDFF and MASLD case–control status identifies two single variants and two gene-level associations in APOB, CDH5, MYCBP2, and XAB2. Association testing with predicted phenotypes, which replicates more known genetic variants from GWAS than true phenotypes, identifies 16 single variants and 11 gene-level associations implicating 23 additional genes. Two variants were polymorphic only among African ancestry participants and several associations showed significant heterogeneity in ancestry and sex-stratified analyses. In total, we identified 27 genes, of which 3 are monogenic causes of steatosis (APOB, G6PC1, PPARG), 4 were previously associated with MASLD (APOB, APOC3, INSR, PPARG), and 23 had supporting clinical, experimental, and/or genetic evidence.ConclusionsOur results suggest that trans-ancestral association analyses can identify ancestry-specific rare and ultra-rare coding variants in MASLD pathogenesis. Furthermore, we demonstrate the utility of machine learning in genetic investigations of difficult-to-phenotype diseases in trans-ancestral biobanks.

Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients.

Ataxia telangiectasia and Rad3-related (ATR) kinase and its interacting protein ATRIP orchestrate the replication stress response. Homozygous splice variants in the ATRIP gene, resulting in ATRIP deficiency, were identified in two patients of independent ancestry with microcephaly, primordial dwarfism, and recurrent infections. The c.829+5G>T patient exhibited lymphopenia, poor vaccine responses, autoimmune features with hemolytic anemia, and neutropenia. Immunophenotyping revealed reduced CD16+/CD56dim NK cells and absent naïve T cells, MAIT cells, and iNKT cells. Lymphocytic defects were characterized by TCR oligoclonality, abnormal class switch recombination, and impaired T cell proliferation. ATRIP deficiency resulted in low-grade ATR activation but impaired CHK1 phosphorylation under genotoxic stress. ATRIP-deficient cells inadequately regulated DNA replication, leading to chromosomal instability, compromised cell cycle control, and impaired cell viability. CRISPR-SelectTIME confirmed reduced cell fitness for both variants. This study establishes ATRIP deficiency as a monogenic cause of microcephalic primordial dwarfism, highlights ATRIP's critical role in protecting immune cells from replication stress, and offers new insights into its canonical functions.

Monogenic Common Variable Immunodeficiency (Mo-CVID) Score for Optimizing the Genetic Diagnosis in Pediatric CVID Cohort.

Common variable immunodeficiency (CVID) represents an "umbrella" diagnosis due to its clinical and immunological heterogeneity. The primary objective of this study was to describe a cohort of CVID pediatric subjects from clinical, immunological, and genetic viewpoints. Secondary, we propose a model for prioritizing genetic investigations in these patients. Thirty-four patients with CVID followed at Meyer Children's Hospital, IRCSS, were enrolled. Whole exome sequencing was performed according to the latest International Union of Immunological Societies 2022 update. Genetic variants were identified in 16 patients (47%), including known variants in SLC39A7, PRKCD, STAT3, NFKB1, PIK3R1, PLCG2, RFXANK, PRKDC, TNFRSF13B, and novel variants in SPI1, NFKB1, NFKB2. Comparing the Gene+ and Gene- cohorts, we demonstrated that a monogenic cause is more likely to be found in cases of early disease onset, positive family history, autoimmunity, lymphoproliferation, and specific immunological alterations. Using these criteria, we developed a pediatric monogenic CVID (Mo-CVID) score to hypothesize when a CVID pediatric patient is more likely to carry a genetic mutation. A scoring system such as the Mo-CVID score could help physicians prioritize genetic testing. Genetic analysis in CVID patients can help stratify patients into different disease entities to predict complications and prognosis, ensure appropriate genetic counseling, and personalize treatment.

A tiered approach to exome sequencing analysis in early-onset Primary Ovarian Insufficiency.

Establishing the genetic basis of early-onset primary ovarian insufficiency (EO-POI, <25 years) is important, but defining variant pathogenicity is challenging. To elucidate the genetic architecture of EO-POI in a unique, large cohort. Young women with EO-POI (n=149; n=31 familial, n=118 sporadic) attending a specialist reproductive unit. Exome sequencing was performed. After filtering, variants were retained which were 1) rare/novel (minor allele frequency <0.01%); 2) predicted pathogenic/likely pathogenic; and 3) enriched in the cohort. Each variant was assigned to a category: Category 1, variants in Genomics England Primary Ovarian Insufficiency PanelApp genes (n=69); Category 2, variants in other POI-associated genes (n=355) or Category 1 variants following unexpected inheritance patterns; and Category 3, homozygous variants in novel candidate POI genes. A total of 127 Category 1 or 2 variants were identified in 74 different genes (heterozygous 30.9%; homozygous 9.4%; polygenic 21.8%). In familial EO-POI, 64.7% (11/17 kindred) had a Category 1 or 2 variant identified (homozygous: STAG3, MCM9, PSCM3IP, YTHDC2, ZSWIM7; heterozygous: POLR2C, NLRP11, IGSF10, PRKD1, PLEC; polygenic: PDE3A, POLR2H, MSH6, CLPP). In sporadic EO-POI, 63.6% (n=75/118) women had a variant identified (21.2% (n=25) Category 1; 42.4% (n=50) Category 2). Novel POI candidate genes (Category 3) included PCIF1, DND1, MEF2A, MMS22L, RXFP3, C4orf33, and ARRB1. The genetic basis of EO-POI is complex and affected genes span ovarian developmental processes from fetal life to adulthood. Establishing the pathogenicity of individual heterozygous variants can be challenging. However, some women have clear monogenic causes, particularly in familial POI with autosomal recessive inheritance. Others have potential polygenic causes. We describe novel candidate POI genes warranting further exploration.

PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors.

Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (ventriculomegaly) is a defining feature of congenital hydrocephalus (CH) and an under-recognized concomitant of autism. Here, we show that de novo mutations in the autism risk gene PTEN are among the most frequent monogenic causes of CH and primary ventriculomegaly. Mouse Pten-mutant ventriculomegaly results from aqueductal stenosis due to hyperproliferation of periventricular Nkx2.1+ neural progenitor cells (NPCs) and increased CSF production from hyperplastic choroid plexus. Pten-mutant ventriculomegalic cortices exhibit network dysfunction from increased activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or postnatal everolimus treatment corrects ventriculomegaly, rescues cortical deficits and increases survival by antagonizing mTORC1-dependent Nkx2.1+ NPC pathology. Thus, PTEN mutations concurrently alter CSF dynamics and cortical networks by dysregulating Nkx2.1+ NPCs. These results implicate a nonsurgical treatment for CH, demonstrate a genetic association of ventriculomegaly and ASD, and help explain neurodevelopmental phenotypes refractory to CSF shunting in select individuals with CH.

Impaired thalamic burst firing in Fragile X syndrome.

The thalamus performs a critical role in sensory processing by gating the flow of sensory information to the neocortex and directing sensory-driven behaviors; functions which are disrupted in people with autism spectrum disorders (ASD). We have identified cellular changes in thalamic neurons in a mouse model of Fragile X syndrome (FX), the leading monogenic cause of ASD, that alter how the thalamus transmits sensory information to neocortical circuits. In awake animals, thalamic relay cells gate input by shifting between two firing modes: burst and tonic. Relay cells in FX mice, however, do not shift between these modes and instead operate primarily in the tonic mode. We demonstrate that the lack of burst mode firing is caused by a shift in the voltage sensitivity for the Ca 2+ -dependent low threshold spike, which underlies normal burst firing.

GATAD2B-related developmental and epileptic encephalopathy (DEE): Extending the epilepsy phenotype and a literature appraisal.

Heterozygous pathogenic variants in GATAD2B gene have been related to the GATAD2B-associated neurodevelopmental disorders (GAND) characterized by neurodevelopmental delay with predominant language impairment, infantile hypotonia, macrocephaly, ophthalmological abnormalities, and dysmorphic facial features with nonspecific findings on brain magnetic resonance imaging (MRI). Occasionally, affected individuals exhibit drug responsive epilepsy, psychiatric disorders, and other extra-neurological comorbidities. We report a patient carrying a de novo heterozygous missense variant in GATAD2B gene. She presents a developmental and epileptic encephalopathy (DEE) with drug-resistant atypical absences. An extensive review of the literature did not show any similar phenotype. Our report broadens the electroclinical spectrum related to GATAD2B pathogenic variants and supports the inclusion of this monogenic etiology among the genetic causes of epilepsy with drug-resistant atypical absences, a group with few known genetic etiologies. PLAIN LANGUAGE SUMMARY: We describe a patient with drug-resistant atypical absences caused by a pathogenic variant in the GATAD2B gene. Mutations in the GATAD2B gene should be considered among the rare monogenic causes of atypical absences.

Deciphering the digenic architecture of congenital heart disease using trio exome sequencing data.

Deciphering the digenic architecture of congenital heart disease using trio exome sequencing data.

Updated MDSGene review on the clinical and genetic spectrum of LRRK2 variants in Parkinson´s disease

Pathogenic variants in the LRRK2 gene are one of the most commonly identifiable monogenic causes of Parkinson´s disease (PD, PARK-LRRK2). This systematic MDSGene literature review comprehensively summarizes published demographic, clinical, and genetic findings related to LRRK2 variants (https://www.mdsgene.org/). Data on 4660 individuals with 283 different variants were curated. The median age at onset in the PD patients with available information was 56 years, notably, with approximately one-third having PD onset <50 years. Tremor was the most frequently reported initial symptom and more common than reported in other dominantly inherited forms of PD. Of the 211 potentially PD-causing variants, 25 were classified as pathogenic or likely pathogenic, and the remaining 186 (88.2%) were variants of uncertain significance. p.G2019S was the most frequently reported pathogenic variant, followed by p.R1441G and p.R1441C. This systematic review represents the most extensive database on PARK-LRRK2 to date and provides a vital resource to improve precision medicine.

Kidney Stones in Children: Causes,Consequences,and Concerns.

The prevalence of kidney stones (nephrolithiasis) in children has been steadily rising in the last two decades. The commonly reported environmental causes for this rise in the prevalence of nephrolithiasis include obesity, increased intake of fructose-containing energy drinks, increased sodium content in junk foods, decrease in water intake as well as poor oral calcium intake, and increasing usage of antibiotics that deplete the oxalate-metabolizing bacteria in the gut. Increased detection of monogenic causes of nephrolithiasis is being facilitated with the easy availability of next-generation sequencing (NGS). These include primary hyperoxaluria types 1, 2 and 3, hypercalciuria (including monogenic and idiopathic types), hyperuricosuria (including Lesch-Nyhan syndrome, and urate transporter defects, etc.), cystinuria, hereditary xanthinurias, adenine phosphoribosyl transferase (APRT) deficiency (causing 2, 8 dihydroxyadenine stones) etc. The evaluation of pediatric nephrolithiasis includes a comprehensive history taking, examination, basic imaging using renal ultrasound, metabolic evaluation and genetic testing. The recurrence risk for kidney stone occurrence in children is high, placing them at risk for severe morbidities including renal colic, urinary tract infections, acute kidney injury and chronic kidney disease. The management of nephrolithiasis in children necessitates a multidisciplinary approach involving pediatricians, pediatric nephrologists,urologists,dietitians,and nurses.While medical advancements offer effective treatments for kidney stones in children,prioritizing prevention and accurate diagnosis with the usage of appropriate genetic and metabolic work-up remains crucial for optimal management.

Phosphorylation of CRYAB induces a condensatopathy to worsen post-myocardial infarction left ventricular remodeling.

Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart failure syndromes remains mechanistically unexamined. We observed mis-localization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by R120G mutation in the cognate chaperone protein, CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine-59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phospho-mimetic mutation of serine-59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity, and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knock-in was sufficient to induce desmin mis-localization and myocardial protein aggregates, while S59A CRYAB knock-in rescued left ventricular systolic dysfunction post-myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine-59 phosphorylation and rescued post-myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.

Monogenic disorders associated with motor speech phenotypes in children and adolescents undergoing clinical exome sequencing.

Monogenic disorders associated with motor speech phenotypes in children and adolescents undergoing clinical exome sequencing.

Systematic Review, Meta-Analysis, and Population Study to Determine the Biologic Sex Ratio in Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) appears to be diagnosed twice as often in male than in female patients. This could be attributed to underdiagnosis in female patients or sex differences in susceptibility. Up to 30% of cases have an autosomal dominant monogenic cause, where equal sex prevalence would be expected. The aim of this systematic review, meta-analysis, and population study was to assess the sex ratio in patients with DCM, stratified by genetic status, and evaluate whether this is influenced by diagnostic bias. A literature search identified DCM patient cohorts with discernible sex ratios. Exclusion criteria were studies with a small (n<100), pediatric, or peripartum population. Meta-analysis and metaregression compared the proportion of female participants for an overall DCM cohort and the following subtypes: all genetic DCM, individual selected DCM genes (TTN and LMNA), and gene-elusive DCM. Population DCM sex ratios generated from diagnostic codes were also compared with those from sex-specific means using the UK Biobank imaging cohort; this established ICD coded, novel imaging-first, and genotype first determined sex ratios. A total of 99 studies, with 37 525 participants, were included. The overall DCM cohort had a 0.30 female proportion (95% CI, 0.28-0.32), corresponding to a male:female ratio (M:F) of 2.38:1. This was similar to patients with an identified DCM variant (0.31 [95% CI, 0.26-0.36]; M:F 2.22:1; P=0.56). There was also no significant difference when compared with patients with gene-elusive DCM (0.30 [95% CI, 0.24-0.37]; M:F 2.29:1; P=0.81). Furthermore, the ratio within autosomal dominant gene variants was not significantly different for TTN (0.28 [95% CI, 0.22-0.36]; M:F 2.51:1; P=0.82) or LMNA (0.35 [95% CI, 0.27-0.44]; M:F 1.84:1; P=0.41). Overall, the sex ratio for DCM in people with disease attributed to autosomal dominant gene variants was similar to the all-cause group (0.34 [95% CI, 0.28-0.40]; M:F 1.98:1; P=0.19). In the UK Biobank (n=47 549), DCM defined by International Classification of Diseases, 10th revision, coding had 4.5:1 M:F. However, implementing sex-specific imaging-first and genotype-first diagnostic approaches changed this to 1.7:1 and 2.3:1, respectively. This study demonstrates that DCM is twice as prevalent in male patients. This was partially mitigated by implementing sex-specific DCM diagnostic criteria. The persistent male excess in genotype-positive patients with an equally prevalent genetic risk suggests additional genetic or environmental drivers for sex-biased penetrance. URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42023451944.

How (Ultra-)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases.

The aim of this study was to explore the impact of rare and ultra-rare genetic variants on the understanding and treatment of autoimmune and autoinflammatory diseases with a focus on systemic lupus erythematosus (SLE) and Behçet syndrome. This review summarizes current research on the monogenic causes of SLE and Behçet syndrome, highlighting the various pathways that can be responsible for these unique phenotypes. In monogenic SLE, the identification of complement and DNASE1L3 deficiencies has elucidated mechanisms of apoptotic body accumulation and extracellular nucleic acid sensing. Type I interferonopathies underline the specific role of DNA/RNA sensing and the interferon overexpression in the development of systemic autoimmunity. Other significant genetic defects include Toll-like receptor hypersignaling and JAK/STATopathies, which contribute to the breakdown of immune tolerance. To date, genetic defects directly affecting B and T cell biology only account for a minority of identified causes of monogenic lupus, highlighting the importance of a tight regulation of mechanistic target of rapamycin and RAS (Rat sarcoma GTPase)/MAPK (mitogen-activated protein kinase) signaling in lupus. In Behçet syndrome, rare variants in TNFAIP3, RELA, and NFKB1 genes have been identified, underscoring the importance of NF-κB overactivation. Additional monogenic diseases such as ELF4, WDR1 mutations and trisomy 8 further illustrate the genetic complexity of this condition. Observations from genetic studies in SLE and Behçet syndrome highlight the complexity of systemic inflammatory diseases in which distinct molecular defects caused by single-gene mutations can promote lupus or Behçet syndromes, often unrecognizable from their genetically complex "classical" forms. Insights gained from studying rare genetic variants enhance our understanding of immune function in health and disease, paving the way for targeted therapies and personalized medicine.

Management of genetically determined kidney stone disease: consensus from a panel of urologists and nephrologists.

Available evidence suggests that monogenic causes of kidney stones are likely under-diagnosed, particularly in young adults, needing expert multidisciplinary recommendations to improve diagnosis, management and therapeutic outcomes. To increase the awareness among the medical community on the recognition of the signs and symptoms of genetically determined kidney stone disease in adult patients, with a special focus on primary hyperoxaluria (PH), a group of nephrologists and urologists started a consensus process through the Delphi method. A list of 40 statements (23 regarding genetically determined stone disease and 17 regarding primary hyperoxaluria) was defined by the authors and included in an online Delphi survey, which was sent to 16 urologists and 22 nephrologists with expertise in managing patients with kidney stone disease. An agreement threshold of 75% was established for consensus. After two rounds of Delphi voting, consensus was reached for 33 statements, 18 regarding genetically determined stone disease and 15 regarding PH. The Delphi process highlighted several areas of agreement with regard to the characteristic or anamnestic data suggesting diagnostic investigation, optimal diagnostic patterns, treatment strategies and management of patients with genetically determined nephrolithiasis. The process also highlighted some grey areas, which deserve further investigation and highlight the need for educational initiatives focused on rare diseases in the field of kidney stones.

Targeted exonic sequencing identifies novel variants in a cerebral small vessel disease cohort.

Targeted exonic sequencing identifies novel variants in a cerebral small vessel disease cohort.

Tsc1 Deletion in Purkinje Neurons Disrupts the Axon Initial Segment, Impairing Excitability and Cerebellar Function.

Loss-of-function mutations in tuberous sclerosis 1 ( TSC1 ) are prevalent monogenic causes of autism spectrum disorder (ASD). Selective deletion of Tsc1 from mouse cerebellar Purkinje neurons has been shown to cause several ASD-linked behavioral impairments, which are linked to reduced Purkinje neuron repetitive firing rates. We used electrophysiology methods to investigate why Purkinje neuron-specific Tsc1 deletion ( Tsc1 mut/mut ) impairs Purkinje neuron firing. These studies revealed a depolarized shift in action potential threshold voltage, an effect that we link to reduced expression of the fast-transient voltage-gated sodium (Nav) current in Tsc1 mut/mut Purkinje neurons. The reduced Nav currents in these cells was associated with diminished secondary immunofluorescence from anti-pan Nav channel labeling at Purkinje neuron axon initial segments (AIS). Interestingly, anti-ankyrinG immunofluorescence was also found to be significantly reduced at the AIS of Tsc1 mut/mut Purkinje neurons, suggesting Tsc1 is necessary for the organization and functioning of the Purkinje neuron AIS. An analysis of the 1 st and 2 nd derivative of the action potential voltage-waveform supported this hypothesis, revealing spike initiation and propagation from the AIS of Tsc1 mut/mut Purkinje neurons is impaired compared to age-matched control Purkinje neurons. Heterozygous Tsc1 deletion resulted in no significant changes in the firing properties of adult Purkinje neurons, and slight reductions in anti-pan Nav and anti-ankyrinG labeling at the Purkinje neuron AIS, revealing deficits in Purkinje neuron firing due to Tsc1 haploinsufficiency are delayed compared to age-matched Tsc1 mut/mut Purkinje neurons. Together, these data reveal the loss of Tsc1 impairs Purkinje neuron firing and membrane excitability through the dysregulation of proteins necessary for AIS organization and function.

Abstract TP373: Impaired resting state functional connectivity in CADASIL mutant mice

Objectives: Cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is a leading monogenic cause of cerebral small-vessel disease. This study aimed to evaluate the functional integrity of long white matter tracts in CADASIL transgenic mice and assess the potential of tocotrienol (T3) as a therapeutic agent. Methods: Optical resting-state functional connectivity imaging and behavioral examinations were employed to characterize white matter tracts in CADASIL transgenic mice, both with and without focal white matter lesions in the corpus callosum. Functional connectivity and behavioral outcomes were compared between Notch3 R169C and Notch3 WT mice. The efficacy of T3, a neuroprotective vitamin E derivative, was also evaluated based on findings from previous clinical trials in small vessel disease. Results: After performing stepwise elimination using the Akaike Information Criterion (AIC), the diet variable was removed from the model and we pooled the data in the two diet arms for subsequent analyses of interhemispheric homotopic connectivity. At baseline, resting-state interhemispheric functional connectivity was significantly reduced in Notch3 R169C mice compared to Notch3 WT mice (p=0.004). No significant differences between genotypes were observed on day 1 and day 7 post-lesion. Behavioral analysis using the grid walk test revealed an increased number of foot faults in Notch3 R169C mice at baseline, with similar increases observed in both genotypes one week after lesion induction. Lesion volumes on day 7 did not differ between genotypes. Conclusions: The Notch3 R169C CADASIL model demonstrated impaired resting-state functional connectivity and increased foot faults, indicating significant functional and behavioral deficits. Future research will focus on evaluating therapeutic and preventive interventions in CADASIL models using these parameters.

Tsc1 deletion in Purkinje neurons disrupts the axon initial segment, impairing excitability and cerebellar function.

Tsc1 deletion in Purkinje neurons disrupts the axon initial segment, impairing excitability and cerebellar function.