Yon Ho Jee, Florian Thibord, Alicia Dominguez, Corriene Sept, Kristin Boulier, Vidhya Venkateswaran, Yi Ding, Tess Cherlin, Shefali Setia Verma, Valeria Lo Faro, Traci M Bartz, Anne Boland, Jennifer A Brody, Jean-Francois Deleuze, Joseph Emmerich, Marine Germain, Andrew D Johnson, Charles Kooperberg, Pierre-Emmanuel Morange, Nathan Pankratz, Bruce M Psaty, Alexander P Reiner, David M Smadja, Colleen M Sitlani, Pierre Suchon, Weihong Tang, David-Alexandre Trégouët, Sebastian Zöllner, Bogdan Pasaniuc, Scott M Damrauer, Serena Sanna, Harold Snieder, Christopher Kabrhel, Nicholas L Smith, Peter Kraft
Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations...
June 16, 2024: Human Molecular Genetics
Motoko Unoki, Shuhei Uemura, Akihiro Fujimoto, Hiroyuki Sasaki
We have recently discovered that the so-called subcortical maternal complex (SCMC) proteins composing of cytoplasmic lattices are destabilized in Uhrf1 knockout murine fully grown oocytes (FGOs). Here we report that human UHRF1 interacts with human NLRP5 and OOEP, which are core components of the SCMC. Moreover, NLRP5 and OOEP interact with DPPA3, which is an essential factor for exporting UHRF1 from the nucleus to the cytoplasm in oocytes. We identify that NLRP5, not OOEP, stabilizes UHRF1 protein in the cytoplasm utilizing specifically engineered cell lines mimicking UHRF1 status in oocytes and preimplantation embryos...
June 13, 2024: Human Molecular Genetics
Nancy Alnassar, Jacek Hajto, Robin M H Rumney, Suraj Verma, Malgorzata Borczyk, Chandrika Saha, Janos Kanczler, Arthur M Butt, Annalisa Occhipinti, Joanna Pomeroy, Claudio Angione, Michal Korostynski, Dariusz C Górecki
Alterations in Dp71 expression, the most ubiquitous dystrophin isoform, have been associated with patient survival across tumours. Intriguingly, in certain malignancies, Dp71 acts as a tumour suppressor, while manifesting oncogenic properties in others. This diversity could be explained by the expression of two Dp71 splice variants encoding proteins with distinct C-termini, each with specific properties. Expression of these variants has impeded the exploration of their unique roles. Using CRISPR/Cas9, we ablated the Dp71f variant with the alternative C-terminus in a sarcoma cell line not expressing the canonical C-terminal variant, and conducted molecular (RNAseq) and functional characterisation of the knockout cells...
June 9, 2024: Human Molecular Genetics
Karen N McFarland, Anjana Tiwari, Vera Hashem, Linwei Zhang, Desmond Zeng, Justin Vincent, Maria J Arredondo, Kristy L Johnson, Shi Rui Gan, Ichiro Yabe, Laurits Skov, Astrid Rasmussen, Tetsuo Ashizawa
Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant ataxia caused by a large expansion of the (ATTCT)n repeat in ATXN10. SCA10 was described in Native American and Asian individuals which prompted a search for an expanded haplotype to confirm a common ancestral origin for the expansion event. All patients with SCA10 expansions in our cohort share a single haplotype defined at the 5'-end by the minor allele of rs41524547, located ~35 kb upstream of the SCA10 expansion. Intriguingly, rs41524547 is located within the miRNA gene, MIR4762, within its DROSHA cleavage site and just outside the seed sequence for mir4792-5p...
June 4, 2024: Human Molecular Genetics
(no author information available yet)
No abstract text is available yet for this article.
June 4, 2024: Human Molecular Genetics
(no author information available yet)
No abstract text is available yet for this article.
May 31, 2024: Human Molecular Genetics
Abraham Shim, Xiaohan Luan, Wen Zhou, Yanick J Crow, John Maciejowski
The cGAS-STING pathway detects cytosolic DNA and activates a signaling cascade that results in a type I interferon (IFN) response. The endoplasmic reticulum (ER)-associated exonuclease TREX1 suppresses cGAS-STING by eliminating DNA from the cytosol. Mutations that compromise TREX1 function are linked to autoinflammatory disorders, including systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS). Despite key roles in regulating cGAS-STING and suppressing excessive inflammation, the impact of many disease-associated TREX1 mutations-particularly those outside of the core catalytic domains-remains poorly understood...
May 25, 2024: Human Molecular Genetics
Nasrin Pazoki, Mitra Salehi, Seyed Abdolhamid Angaji, Meghdad Abdollahpour-Alitappeh
BACKGROUND: Genetic abnormalities like Y chromosome microdeletions are implicated in male infertility. This study investigated the association of azoospermia factor (AZF) region microdeletions with unsuccessful assisted reproductive techniques (ART), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). METHODS: This cross-sectional analysis study examined 80 Iranian oligospermic men (mean age 34 years) with prior failed ICSI and IVF cycles (IR...
May 25, 2024: Human Molecular Genetics
Zhong-Qiu Yu, Jenny Carmichael, Galen A Collins, Maria Daniela D'Agostino, Mathieu Lessard, Helen V Firth, Pooja Harijan, Andrew E Fry, John Dean, Jiuchun Zhang, Usha Kini, Alfred L Goldberg, David C Rubinsztein
The ubiquitin-proteasome system mediates the degradation of a wide variety of proteins. Proteasome dysfunction is associated with neurodegenerative diseases and neurodevelopmental disorders in humans. Here we identified mutations in PSMC5, an AAA ATPase subunit of the proteasome 19S regulatory particle, in individuals with neurodevelopmental disorders, which were initially considered as variants of unknown significance. We have now found heterozygotes with the following mutations: P320R (6 individuals), R325W, Q160A, and one nonsense mutation at Q69...
May 22, 2024: Human Molecular Genetics
Andrew Jiang, Linya You, Renee R Handley, Victoria Hawkins, Suzanne J Reid, Jessie C Jacobsen, Stefano Patassini, Skye R Rudiger, Clive J Mclaughlan, Jennifer M Kelly, Paul J Verma, C Simon Bawden, James F Gusella, Marcy E MacDonald, Henry J Waldvogel, Richard L M Faull, Klaus Lehnert, Russell G Snell
Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course-modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. The 73 polyglutamine repeat is somatically stable and therefore likely captures a prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss...
May 22, 2024: Human Molecular Genetics
Giulia Emanuelli, JiaYi Zhu, Wei Li, Nicholas W Morrell, Stefan J Marciniak
Pulmonary arterial hypertension (PAH) is a disorder with a large genetic component. Biallelic mutations of EIF2AK4, which encodes the kinase GCN2, are causal in two ultra-rare subtypes of PAH, pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis. EIF2AK4 variants of unknown significance have also been identified in patients with classical PAH, though their relationship to disease remains unclear. To provide patients with diagnostic information and enable family testing, the functional consequences of such rare variants must be determined, but existing computational methods are imperfect...
May 22, 2024: Human Molecular Genetics
Kacie J Meyer, John H Fingert, Michael G Anderson
PURPOSE: Exfoliation syndrome (XFS) is a systemic disease of elastin-rich tissues involving a deposition of fibrillar exfoliative material (XFM) in the anterior chamber of the eye, which can promote glaucoma. The purpose of this study was to create mice with CRISPR/Cas9-induced variations in candidate genes identified from human genome-wide association studies (GWAS) and screen them for indices of XFS. METHODS: Variants predicted to be deleterious were sought in the Agpat1, Cacna1a, Loxl1, Pomp, Rbms3, Sema6a, and Tlcd5 genes of C57BL/6J mice using CRISPR/Cas9-based gene editing...
May 20, 2024: Human Molecular Genetics
Giulia Massaro, Amy F Geard, Hemanth R Nelvagal, Katrina Gore, Nadine K Clemo, Simon N Waddington, Ahad A Rahim
Gaucher Disease (GD) is an inherited metabolic disorder caused by mutations in the GBA1 gene. It can manifest with severe neurodegeneration and visceral pathology. The most acute neuronopathic form (nGD), for which there are no curative therapeutic options, is characterised by devastating neuropathology and death during infancy. In this study, we investigated the therapeutic benefit of systemically delivered AAV9 vectors expressing the human GBA1 gene at two different doses comparing a neuronal-selective promoter with ubiquitous promoters...
May 16, 2024: Human Molecular Genetics
Taiju Fujii, Luxiaoxue Liang, Kazuhisa Nakayama, Yohei Katoh
Primary cilia are antenna-like structures protruding from the surface of various eukaryotic cells, and have distinct protein compositions in their membranes. This distinct protein composition is maintained by the presence of the transition zone (TZ) at the ciliary base, which acts as a diffusion barrier between the ciliary and plasma membranes. Defects in cilia and the TZ are known to cause a group of disorders collectively called the ciliopathies, which demonstrate a broad spectrum of clinical features, such as perinatally lethal Meckel syndrome (MKS), relatively mild Joubert syndrome (JBTS), and nonsyndromic nephronophthisis (NPHP)...
May 15, 2024: Human Molecular Genetics
Adam K Dziulko, Holly Allen, Edward B Chuong
Speckled Protein 140 (SP140) is a chromatin reader with critical roles regulating immune cell transcriptional programs, and SP140 splice variants are associated with immune diseases including Crohn's disease, multiple sclerosis, and chronic lymphocytic leukemia. SP140 expression is currently thought to be restricted to immune cells. However, by analyzing human transcriptomic datasets from a wide range of normal and cancer cell types, we found recurrent cancer-specific expression of SP140, driven by an alternative intronic promoter derived from an intronic endogenous retrovirus (ERV)...
May 15, 2024: Human Molecular Genetics
Min-Zhi Jiang, Sheila M Gaynor, Xihao Li, Eric Van Buren, Adrienne Stilp, Erin Buth, Fei Fei Wang, Regina Manansala, Stephanie M Gogarten, Zilin Li, Linda M Polfus, Shabnam Salimi, Joshua C Bis, Nathan Pankratz, Lisa R Yanek, Peter Durda, Russell P Tracy, Stephen S Rich, Jerome I Rotter, Braxton D Mitchell, Joshua P Lewis, Bruce M Psaty, Katherine A Pratte, Edwin K Silverman, Robert C Kaplan, Christy Avery, Kari E North, Rasika A Mathias, Nauder Faraday, Honghuang Lin, Biqi Wang, April P Carson, Arnita F Norwood, Richard A Gibbs, Charles Kooperberg, Jessica Lundin, Ulrike Peters, Josée Dupuis, Lifang Hou, Myriam Fornage, Emelia J Benjamin, Alexander P Reiner, Russell P Bowler, Xihong Lin, Paul L Auer, Laura M Raffield
Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1)...
May 15, 2024: Human Molecular Genetics
Akifumi Nozawa, Taiki Abe, Tetsuya Niihori, Michio Ozeki, Yoko Aoki, Hidenori Ohnishi
Generalized lymphatic anomaly (GLA) and kaposiform lymphangiomatosis (KLA) are rare congenital disorders that arise through anomalous embryogenesis of the lymphatic system. A somatic activating NRAS p.Q61R variant has been recently detected in GLA and KLA tissues, suggesting that the NRAS p.Q61R variant plays an important role in the development of these diseases. To address this role, we studied the effect of the NRAS p.Q61R variant in lymphatic endothelial cells (LECs) on the structure of the lymphatics during embryonic and postnatal lymphangiogenesis applying inducible, LEC-specific NRAS p...
May 13, 2024: Human Molecular Genetics
Ksenia S Marinina, Ilya B Bezprozvanny, Polina A Egorova
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is reported to be the most common type of autosomal dominant cerebellar ataxia (ADCA). SCA3 patients suffer from a progressive decline in motor coordination and other disease-associated symptoms. Moreover, recent studies have reported that SCA3 patients also exhibit symptoms of cerebellar cognitive affective syndrome (CCAS). We previously observed signs of CCAS in mouse model of SCA3. Particularly, SCA3-84Q mice suffer from anxiety, recognition memory decline, and also exhibit signs of low mood and aversion to activity...
May 10, 2024: Human Molecular Genetics
Kaicheng Zhou, Wenxuan Li, Lu Chen, Siyue Chen, Mengxing Liu, Zhicong Yang, Zhanrui Mao, Wenqiang Yu
microRNAs (miRNAs) are short non-coding RNAs that have been increasingly recognized for their significant roles in the progression of cancer. Distinct miRNAs exhibit diverse functions attributed to variations in their sequences. As a result of possessing highly homologous seed sequences, these miRNAs target overlapping or similar gene sets, thus performing analogous roles. However, different from this sight, our study discovered that miR-135a-5p and miR-135b-5p, despite differing by only one nucleotide, exhibit distinct functional roles...
May 9, 2024: Human Molecular Genetics
Chantal A Coles, Keryn G Woodman, Elizabeth M Gibbs, Rachelle H Crosbie, Jason D White, Shireen R Lamandé
Duchenne Muscular Dystrophy (DMD) is a progressive and fatal neuromuscular disease. Cycles of myofibre degeneration and regeneration are hallmarks of the disease where immune cells infiltrate to repair damaged skeletal muscle. Benfotiamine is a lipid soluble precursor to thiamine, shown clinically to reduce inflammation in diabetic related complications. We assessed whether benfotiamine administration could reduce inflammation related dystrophic pathology. Benfotiamine (10 mg/kg/day) was fed to male mdx mice (n = 7) for 15 weeks from 4 weeks of age...
May 6, 2024: Human Molecular Genetics
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