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Proceedings of the National Academy of... Jun 2024Alcohol dehydrogenase 1B (ADH1B) is a primate-specific enzyme which, uniquely among the ADH class 1 family, is highly expressed both in adipose tissue and liver. Its...
Alcohol dehydrogenase 1B (ADH1B) is a primate-specific enzyme which, uniquely among the ADH class 1 family, is highly expressed both in adipose tissue and liver. Its expression in adipose tissue is reduced in obesity and increased by insulin stimulation. Interference with expression has also been reported to impair adipocyte function. To better understand the role of ADH1B in adipocytes, we used CRISPR/Cas9 to delete in human adipose stem cells (ASC). Cells lacking ADH1B failed to differentiate into mature adipocytes manifested by minimal triglyceride accumulation and a marked reduction in expression of established adipocyte markers. As ADH1B is capable of converting retinol to retinoic acid (RA), we conducted rescue experiments. Incubation of ADH1B-deficient preadipocytes with 9-cis-RA, but not with all-transretinol, significantly rescued their ability to accumulate lipids and express markers of adipocyte differentiation. A homozygous missense variant in (p.Arg313Cys) was found in a patient with congenital lipodystrophy of unknown cause. This variant significantly impaired the protein's dimerization, enzymatic activity, and its ability to rescue differentiation in ADH1B-deficient ASC. The allele frequency of this variant in the Middle Eastern population suggests that it is unlikely to be a fully penetrant cause of severe lipodystrophy. In conclusion, ADH1B appears to play an unexpected, crucial and cell-autonomous role in human adipocyte differentiation by serving as a necessary source of endogenous retinoic acid.
Topics: Humans; Alcohol Dehydrogenase; Adipogenesis; Adipocytes; Tretinoin; Cell Differentiation; CRISPR-Cas Systems; Mutation, Missense; Adipose Tissue
PubMed: 38838011
DOI: 10.1073/pnas.2319301121 -
Frontiers in Genetics 2024Variants in the gene are a frequent cause of hypertrophic cardiomyopathy (HCM) but display a large phenotypic heterogeneity. Founder mutations are often believed to be...
BACKGROUND
Variants in the gene are a frequent cause of hypertrophic cardiomyopathy (HCM) but display a large phenotypic heterogeneity. Founder mutations are often believed to be more benign as they prevailed despite potential negative selection pressure. We detected a pathogenic variant in (del exon 23-26) in several probands. We aimed to assess the presence of a common haplotype and to describe the cardiac characteristics, disease severity and long-term outcome of mutation carriers.
METHODS
Probands with HCM caused by a pathogenic deletion of exon 23-26 of were identified through genetic screening using a gene panel encompassing 59 genes associated with cardiomyopathies in a single genetic center in Belgium. Cascade screening of first-degree relatives was performed, and genotype positive relatives were further phenotyped. Clinical characteristics were collected from probands and relatives. Cardiac outcomes included death, heart transplantation, life-threatening arrhythmia, heart failure hospitalization or septal reduction therapy. Haplotype analysis, using microsatellite markers surrounding , was performed in all index patients to identify a common haplotype. The age of the founder variant was estimated based on the size of the shared haplotype using a linkage-disequilibrium based approach.
RESULTS
We identified 24 probands with HCM harbouring the exon 23-26 deletion. Probands were on average 51 ± 16 years old at time of clinical HCM diagnosis and 62 ± 10 years old at time of genetic diagnosis. A common haplotype of 1.19 Mb was identified in all 24 probands, with 19 of the probands sharing a 13.8 Mb haplotype. The founder event was estimated to have happened five generations, or 175-200 years ago, around the year 1830 in central Flanders. Through cascade screening, 59 first-degree relatives were genetically tested, of whom 37 (62.7%) were genotype positive (G+) and 22 (37.3%) genotype negative (G-). They were on average 38 ± 19 years old at time of genetic testing. Subsequent clinical assessment revealed a HCM phenotype in 19 (51.4%) G+ relatives. Probands were older (63 ± 10 vs. 42 ± 21 years; < 0.001) and had more severe phenotypes than G+ family members, presenting with more symptoms (50% vs. 13.5%; = 0.002), arrhythmia (41.7% vs. 12.9%, = 0.014), more overt hypertrophy and left ventricular outflow tract obstruction (43.5% vs. 3.0%; < 0.001). Male G+ relatives more often had a HCM phenotype (78.6% vs. 34.8%; = 0.010) and were more severely affected than females. At the age of 50, a penetrance of 78.6% was observed, defined as the presence of HCM in 11 of 14 G+ relatives with age ≥50 years. Overall, 20.3% of all variant carriers developed one of the predefined cardiac outcomes after a median follow-up of 5.5 years with an average age of 50 (±21) years.
CONCLUSION
A Belgian founder variant, an exon 23-26 deletion in , was identified in 24 probands and 37 family members. The variant is characterized by a high penetrance of 78.6% at the age of 50 years but has variable phenotypic expression. Adverse outcomes were observed in 20.3% of patients during follow-up.
PubMed: 38836037
DOI: 10.3389/fgene.2024.1392527 -
Disease Models & Mechanisms May 2024Recent progress in human disease genetics is leading to rapid advances in understanding pathobiological mechanisms. However, the sheer number of risk-conveying genetic... (Review)
Review
Recent progress in human disease genetics is leading to rapid advances in understanding pathobiological mechanisms. However, the sheer number of risk-conveying genetic variants being identified demands in vivo model systems that are amenable to functional analyses at scale. Here we provide a practical guide for using the diploid frog species Xenopus tropicalis to study many genes and variants to uncover conserved mechanisms of pathobiology relevant to human disease. We discuss key considerations in modelling human genetic disorders: genetic architecture, conservation, phenotyping strategy and rigour, as well as more complex topics, such as penetrance, expressivity, sex differences and current challenges in the field. As the patient-driven gene discovery field expands significantly, the cost-effective, rapid and higher throughput nature of Xenopus make it an essential member of the model organism armamentarium for understanding gene function in development and in relation to disease.
Topics: Animals; Xenopus; Humans; Disease Models, Animal; Genetic Diseases, Inborn; Phenotype
PubMed: 38832520
DOI: 10.1242/dmm.050754 -
MedRxiv : the Preprint Server For... May 2024Approximately 3% of the human genome consists of repetitive elements called tandem repeats (TRs), which include short tandem repeats (STRs) of 1-6bp motifs and variable...
Approximately 3% of the human genome consists of repetitive elements called tandem repeats (TRs), which include short tandem repeats (STRs) of 1-6bp motifs and variable number tandem repeats (VNTRs) of 7+bp motifs. TR variants contribute to several dozen mono- and polygenic diseases but remain understudied and "enigmatic," particularly relative to single nucleotide variants. It remains comparatively challenging to interpret the clinical significance of TR variants. Although existing resources provide portions of necessary data for interpretation at disease-associated loci, it is currently difficult or impossible to efficiently invoke the additional details critical to proper interpretation, such as motif pathogenicity, disease penetrance, and age of onset distributions. It is also often unclear how to apply population information to analyses. We present STRchive (S-T-archive, http://strchive.org/ ), a dynamic resource consolidating information on TR disease loci in humans from research literature, up-to-date clinical resources, and large-scale genomic databases, with the goal of streamlining TR variant interpretation at disease-associated loci. We apply STRchive -including pathogenic thresholds, motif classification, and clinical phenotypes-to a gnomAD cohort of ∼18.5k individuals genotyped at 60 disease-associated loci. Through detailed literature curation, we demonstrate that the majority of TR diseases affect children despite being thought of as adult diseases. Additionally, we show that pathogenic genotypes can be found within gnomAD which do not necessarily overlap with known disease prevalence, and leverage STRchive to interpret locus-specific findings therein. We apply a diagnostic blueprint empowered by STRchive to relevant clinical vignettes, highlighting possible pitfalls in TR variant interpretation. As a living resource, STRchive is maintained by experts, takes community contributions, and will evolve as understanding of TR diseases progresses.
PubMed: 38826469
DOI: 10.1101/2024.05.21.24307682 -
Bioorganic Chemistry Aug 2024There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of...
There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of 4'-((4-substituted-4,5-dihydro-1H-1,2,3-triazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile (OTBN-1,2,3-triazole) derivatives were synthesized by click chemistry. The series of bioactive compounds were designed and synthesized from diverse alkynes and N-OTBN, using copper (II) acetate monohydrate in aqueous dimethylformamide at room temperature. Besides being highly cost-effective and significantly reducing synthesis, the reaction yielded 91-98 % of the target products without the need of any additional steps or chromatographic techniques. Two analogues exhibit promising anti-cancer biological activities. Analogue 4l shows highly specific cytostatic activity against lung cancer cells, while analogue 4k exhibits pan-cancer anti-growth activity. A kinase screen suggests compound 4k has single-digit micromolar activity against kinase STK33. High STK33 RNA expression correlates strongly with poorer patient outcomes in both adult and pediatric glioma. Compound 4k potently inhibits cell proliferation, invasion, and 3D neurosphere formation in primary patient-derived glioma cell lines. The observed anti-cancer activity is enhanced in combination with specific clinically relevant small molecule inhibitors. Herein we establish a novel biochemical kinase inhibitory function for click-chemistry-derived OTBN-1,2,3-triazole analogues and further report their anti-cancer activity in vitro for the first time.
Topics: Humans; Triazoles; Click Chemistry; Antineoplastic Agents; Cell Proliferation; Structure-Activity Relationship; Drug Screening Assays, Antitumor; Protein Kinase Inhibitors; Molecular Structure; Protein Serine-Threonine Kinases; Dose-Response Relationship, Drug; Cell Line, Tumor; Nitriles
PubMed: 38824700
DOI: 10.1016/j.bioorg.2024.107485 -
Journal of Neuroimmunology Jul 2024Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare immune-mediated neuropathy for which there is no clearly identified risk factor. The present...
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare immune-mediated neuropathy for which there is no clearly identified risk factor. The present study identified rare variants in the FBXO38 gene in three familial cases of CIDP with response to corticosteroids in three generations with incomplete penetrance, and in an unrelated fourth case with diffuse nerve hypertrophy. FBXO38 may be involved in the regulation of the immunity mediated by CD8 T cells, which have an important role in CIDP pathophysiology, through PD1 degradation. Considering these findings, FBXO38 should be investigated as a potential genetic factor in larger cohorts of patients with CIDP.
Topics: Humans; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Male; Female; Middle Aged; F-Box Proteins; Adult; Pedigree; Aged
PubMed: 38823119
DOI: 10.1016/j.jneuroim.2024.578381 -
Journal of Parkinson's Disease 2024The penetrance of common genetic risk variants for Parkinson's disease (PD) is low. Pesticide exposure increases PD risk, but how exposure affects penetrance is not well...
BACKGROUND
The penetrance of common genetic risk variants for Parkinson's disease (PD) is low. Pesticide exposure increases PD risk, but how exposure affects penetrance is not well understood.
OBJECTIVE
To determine the relationship between occupational pesticide exposure and PD in people with LRRK2 and GBA risk variants.
METHODS
Participants of the Parkinson's Progression Markers Initiative (PPMI) with a LRRK2-G2019 S or GBA risk variant provided information about occupational pesticide exposure. We compared exposure in carriers with and without PD. Among carriers with PD, we used Cox proportional hazard models to compare time-to impairment in balance, cognition, and activities of daily living (ADLs) between participants with and without prior occupational pesticide exposure.
RESULTS
378 participants with a risk variant provided exposure information; 176 with LRRK2-G2019 S (54 with and 122 without PD) and 202 with GBA variants (47 with and 155 without PD). Twenty-six participants reported pesticide exposure. People with a GBA variant and occupational pesticide exposure had much higher odds of PD (aOR: 5.4, 95% CI 1.7-18.5, p < 0.01). People with a LRRK2 variant and a history of occupational pesticide exposure had non-significantly elevated odds of PD (aOR 1.3, 95% CI 0.4-4.6, p = 0.7). Among those with PD, pesticide exposure was associated with a higher risk of balance problems and cognitive impairment in LRRK2-PD and functional impairment in GBA-PD, although associations were not statistically significant.
CONCLUSIONS
Occupational pesticide exposure may increase penetrance of GBA-PD and may be associated with faster symptom progression. Further studies in larger cohorts are necessary.
Topics: Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Female; Parkinson Disease; Male; Glucosylceramidase; Occupational Exposure; Pesticides; Aged; Middle Aged; Penetrance; Activities of Daily Living; Cognitive Dysfunction
PubMed: 38820021
DOI: 10.3233/JPD-240015 -
Frontiers in Pharmacology 2024Breast cancer brain metastasis (BCBM) typically results in an end-stage diagnosis and is hindered by a lack of brain-penetrant drugs. Tumors in the brain rely on the...
Breast cancer brain metastasis (BCBM) typically results in an end-stage diagnosis and is hindered by a lack of brain-penetrant drugs. Tumors in the brain rely on the conversion of acetate to acetyl-CoA by the enzyme acetyl-CoA synthetase 2 (ACSS2), a key regulator of fatty acid synthesis and protein acetylation. Here, we used a computational pipeline to identify novel brain-penetrant ACSS2 inhibitors combining pharmacophore-based shape screen methodology with absorption, distribution, metabolism, and excretion (ADME) property predictions. We identified compounds AD-5584 and AD-8007 that were validated for specific binding affinity to ACSS2. Treatment of BCBM cells with AD-5584 and AD-8007 leads to a significant reduction in colony formation, lipid storage, acetyl-CoA levels and cell survival . In an brain-tumor slice model, treatment with AD-8007 and AD-5584 reduced pre-formed tumors and synergized with irradiation in blocking BCBM tumor growth. Treatment with AD-8007 reduced tumor burden and extended survival . This study identifies selective brain-penetrant ACSS2 inhibitors with efficacy towards breast cancer brain metastasis.
PubMed: 38818373
DOI: 10.3389/fphar.2024.1394685 -
The Oncologist May 2024The prognosis of patients with glioblastoma (GBM) remains poor despite current treatments. Targeted therapy in GBM has been the subject of intense investigation but has...
The prognosis of patients with glioblastoma (GBM) remains poor despite current treatments. Targeted therapy in GBM has been the subject of intense investigation but has not been successful in clinical trials. The reasons for the failure of targeted therapy in GBM are multifold and include a lack of patient selection in trials, the failure to identify driver mutations, and poor blood-brain barrier penetration of investigational drugs. Here, we describe a case of a durable complete response in a newly diagnosed patient with GBM with leptomeningeal dissemination and PTPRZ1-MET fusion who was treated with tepotinib, a brain-penetrant MET inhibitor. This case of successful targeted therapy in a patient with GBM demonstrates that early molecular testing, identification of driver molecular alterations, and treatment with brain-penetrant small molecule inhibitors have the potential to change the outcome in select patients with GBM.
PubMed: 38815166
DOI: 10.1093/oncolo/oyae100 -
Frontiers in Medicine 2024The objective of this study was to investigate the attitudes of healthcare professionals (HPs) working in the prenatal setting toward uncertain results (UR) from...
OBJECTIVE
The objective of this study was to investigate the attitudes of healthcare professionals (HPs) working in the prenatal setting toward uncertain results (UR) from prenatal exome sequencing (pES) in China.
METHODS
We conducted a national survey among HPs working in the prenatal setting. UR in our study include variants of uncertain significance (VUS), variants with variable penetrance/expressivity (VVPE), and secondary findings unrelated to the indication for testing (SFs). A total of 285 questionnaires that met the inclusion criteria were collected. Data were analyzed using IBM SPSS Statistics 26.
RESULTS
When performing the pre-test counseling, only 7.4% of HPs mentioned the possibility of VUS, 6.3% discussed the possibility of VVPE, and 7.4% introduced the SFs with parents with the option to not report these variants. In post-test counseling, 73.0-82.8% HPs discussed with the parents but did not make any recommendations for managing the pregnancy after reporting UR (73.0% for VUS, 82.8% for VVPE, 74.7% for SFs, respectively).
CONCLUSION
Most parents did not have the option of opting out of reporting UR from pES in pre-test counseling. UR did not influence the pregnancy recommendation made by most HPs. Establishing national guidelines for reporting UR from pES and developing strategies to improve counseling skills may help HPs manage UR.
PubMed: 38813373
DOI: 10.3389/fmed.2024.1335649