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Comprehensive phenotypic characterization of an allelic series of zebrafish models of NEB-related nemaline myopathy Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-03-17 Lacramioara Fabian, Esmat Karimi, Gerrie P Farman, Jochen Gohlke, Coen A C Ottenheijm, Hendrikus L Granzier, James J Dowling
Nemaline myopathy (NM) is a rare congenital neuromuscular disorder characterized by muscle weakness and hypotonia, slow gross motor development, and decreased respiratory function. Mutations in at least twelve genes, all of each encode proteins that are either components of the muscle thin filament or regulate its length and stability, have been associated with NM. Mutations in Nebulin (NEB), a giant
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A loss of function mutation in CLDN25 causing Pelizaeus-Merzbacher-like leukodystrophy Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-03-17 Yosuke Hashimoto, Claude Besmond, Nathalie Boddaert, Arnold Munnich, Matthew Campbell
Claudin-25 (CLDN-25), also known as Claudin containing domain 1, is an uncharacterized claudin family member. It has less conserved amino acid sequences when compared to other claudins. It also has a very broad tissue expression profile and there is currently a lack of functional information from murine knockout models. Here, we report a de novo missense heterozygous variant in CLDN25 (c. 745G>C, p
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Reduced synaptic depression in human neurons carrying homozygous disease-causing STXBP1 variant L446F Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-03-15 Miriam Öttl, Ruud F Toonen, Matthijs Verhage
MUNC18-1 is an essential protein of the regulated secretion machinery. De novo, heterozygous mutations in STXBP1, the human gene encoding this protein, lead to a severe neurodevelopmental disorder. Here, we describe the electrophysiological characteristics of a unique case of STXBP1-related disorder caused by a homozygous mutation (L446F). We engineered this mutation in induced pluripotent stem cells
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AIF translocation into nucleus caused by Aifm1 R450Q mutation: generation and characterization of a mouse model for AUNX1 Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-03-07 Tao Shi, Ziyi Chen, Jin Li, Hongyang Wang, Qiuju Wang
Mutations in AIFM1, encoding for apoptosis-inducing factor (AIF), cause AUNX1, an X-linked neurologic disorder with late-onset auditory neuropathy (AN) and peripheral neuropathy. Despite significant research on AIF, there are limited animal models with the disrupted AIFM1 representing the corresponding phenotype of human AUNX1, characterized by late-onset hearing loss and impaired auditory pathways
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Muscle eosinophilia is a hallmark of chronic disease in facioscapulohumeral muscular dystrophy Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-02-10 Andreia M Nunes, Monique M Ramirez, Enrique Garcia-Collazo, Takako Iida Jones, Peter L Jones
Facioscapulohumeral muscular dystrophy (FSHD) is a progressive myopathy caused by the aberrant increased expression of the DUX4 retrogene in skeletal muscle cells. The DUX4 gene encodes a transcription factor that functions in zygotic genome activation and then is silenced in most adult somatic tissues. DUX4 expression in FSHD disrupts normal muscle cell function; however, the downstream pathogenic
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Variants of the promoter of MYH6 gene in congenital isolated and sporadic patent ductus arteriosus: case-control study and cellular functional analyses Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-02-10 Ji-Yang Zuo, Huan-Xin Chen, Qin Yang, Guo-Wei He
Patent ductus arteriosus (PDA) is a common form of congenital heart disease. The MYH6 gene has important effects on cardiovascular growth and development, but the effect of variants in the MYH6 gene promoter on ductus arteriosus is unknown. DNA was extracted from blood samples of 721 subjects (428 patients with isolated and sporadic PDA and 293 healthy controls) and analyzed by sequencing for MYH6
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Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-02-07 Vanitha Nithianandam, Souvarish Sarkar, Mel B Feany
Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction. We created a model of complex I deficiency in the Drosophila
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Excessive tubulin glutamylation leads to progressive cone-rod dystrophy and loss of outer segment integrity Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-02-01 Rawaa Aljammal, Thamaraiselvi Saravanan, Tongju Guan, Scott Rhodes, Michael A Robichaux, Visvanathan Ramamurthy
Mutations in Cytosolic Carboxypeptidase-like Protein 5 (CCP5) are associated with vision loss in humans. To decipher the mechanisms behind CCP5-associated blindness, we generated a novel mouse model lacking CCP5. In this model, we found that increased tubulin glutamylation led to progressive cone-rod dystrophy, with cones showing a more pronounced and earlier functional loss than rod photoreceptors
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Deletion of a conserved genomic region associated with adolescent idiopathic scoliosis leads to vertebral rotation in mice Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-01-27 Jeremy McCallum-Loudeac, Edward Moody, Jack Williams, Georgia Johnstone, Kathleen J Sircombe, Andrew N Clarkson, Megan J Wilson
Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis, in which spinal curvature develops in adolescence, and 90% of patients are female. Scoliosis is a debilitating disease that often requires bracing or surgery in severe cases. AIS affects 2%–5.2% of the population; however, the biological origin of the disease remains poorly understood. In this study, we aimed to determine the
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OPA1 mutation affects autophagy and triggers senescence in autosomal dominant optic atrophy plus fibroblasts Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-01-27 Paola Zanfardino, Alessandro Amati, Stefano Doccini, Sharon N Cox, Apollonia Tullo, Giovanna Longo, Annamaria D’Erchia, Ernesto Picardi, Claudia Nesti, Filippo M Santorelli, Vittoria Petruzzella
In several cases of mitochondrial diseases, the underlying genetic and bioenergetic causes of reduced oxidative phosphorylation (OxPhos) in mitochondrial dysfunction are well understood. However, there is still limited knowledge about the specific cellular outcomes and factors involved for each gene and mutation, which contributes to the lack of effective treatments for these disorders. This study
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Mitochondrial protein synthesis quality control Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-01-27 Lidiia Koludarova, Brendan J Battersby
Human mitochondrial DNA is one of the most simplified cellular genomes and facilitates compartmentalized gene expression. Within the organelle, there is no physical barrier to separate transcription and translation, nor is there evidence that quality control surveillance pathways are active to prevent translation on faulty mRNA transcripts. Mitochondrial ribosomes synthesize 13 hydrophobic proteins
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Removal of pomt1 in zebrafish leads to loss of α-dystroglycan glycosylation and dystroglycanopathy phenotypes Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-01-26 Brittany F Karas, Kristin R Terez, Shorbon Mowla, Namarata Battula, Kyle P Flannery, Brian M Gural, Grace Aboussleman, Numa Mubin, M Chiara Manzini
Biallelic mutations in Protein O-mannosyltransferase 1 (POMT1) are among the most common causes of a severe group of congenital muscular dystrophies (CMDs) known as dystroglycanopathies. POMT1 is a glycosyltransferase responsible for the attachment of a functional glycan mediating interactions between the transmembrane glycoprotein dystroglycan and its binding partners in the extracellular matrix (ECM)
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High throughput functional profiling of genes at intraocular pressure loci reveals distinct networks for glaucoma Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-01-26 Connor J Greatbatch, Qinyi Lu, Sandy Hung, Alexander J Barnett, Kristof Wing, Helena Liang, Xikun Han, Tiger Zhou, Owen M Siggs, David A Mackey, Anthony L Cook, Anne Senabouth, Guei-Sheung Liu, Jamie E Craig, Stuart MacGregor, Joseph E Powell, Alex W Hewitt
Introduction Primary open angle glaucoma (POAG) is a leading cause of blindness globally. Characterized by progressive retinal ganglion cell degeneration, the precise pathogenesis remains unknown. Genome-wide association studies (GWAS) have uncovered many genetic variants associated with elevated intraocular pressure (IOP), one of the key risk factors for POAG. We aimed to identify genetic and morphological
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Challenges and approaches to calibrating patient phenotype as evidence for cancer gene variant classification under ACMG/AMP guidelines Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-01-25 Cristina Fortuno, Kyriaki Michailidou, Michael Parsons, Jill S Dolinsky, Tina Pesaran, Amal Yussuf, Jessica L Mester, Kathleen S Hruska, Susan Hiraki, Robert O’Connor, Raymond C Chan, Serra Kim, Sean V Tavtigian, David Goldgar, Paul A James, Amanda B Spurdle
Since first publication of the American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) variant classification guidelines, additional recommendations for application of certain criteria have been released (https://clinicalgenome.org/docs/), to improve their application in the diagnostic setting. However, none have addressed use of the PS4 and PP4 criteria, capturing
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SPINT2 mutations in the Kunitz domain 2 found in SCSD patients inactivate HAI-2 as prostasin inhibitor via abnormal protein folding and N-glycosylation Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-01-25 Nanxi Huang, Qiaochu Wang, Robert B Bernard, Chao-Yang Chen, Je-Ming Hu, Jehng-Kang Wang, Khee-Siang Chan, Michael D Johnson, Chen-Yong Lin
Mutations in the Kunitz-type serine protease inhibitor HAI-2, encoded by SPINT2, are responsible for the pathogenesis of syndromic congenital sodium diarrhea (SCSD), an intractable secretory diarrhea of infancy. Some of the mutations cause defects in the functionally required Kunitz domain 1 and/or subcellular targeting signals. Almost all SCSD patients, however, harbor SPINT2 missense mutations that
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Regional and bilateral MRI and gene signatures in facioscapulohumeral dystrophy: implications for clinical trial design and mechanisms of disease progression Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-01-25 Chao-Jen Wong, Seth D Friedman, Lauren Snider, Sean R Bennett, Takako I Jones, Peter L Jones, Dennis W W Shaw, Silvia S Blemker, Lara Riem, Olivia DuCharme, Richard J F L Lemmers, Silvère M van der Maarel, Leo H Wang, Rabi Tawil, Jeffrey M Statland, Stephen J Tapscott
Identifying the aberrant expression of DUX4 in skeletal muscle as the cause of facioscapulohumeral dystrophy (FSHD) has led to rational therapeutic development and clinical trials. Several studies support the use of MRI characteristics and the expression of DUX4-regulated genes in muscle biopsies as biomarkers of FSHD disease activity and progression. We performed lower-extremity MRI and muscle biopsies
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Podocyte-specific Nup160 knockout mice develop nephrotic syndrome and glomerulosclerosis Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-01-15 Yuanyuan Li, Chan Xu, Feng Zhao, Qinghong Liu, Xiaojian Qiu, Min Li, Yonghui Yang, Shentong Yu, Huajuan Tong, Lifang Zhang, Bing Chen, Lijuan Qu, Zihua Yu
More than 60 monogenic genes mutated in steroid-resistant nephrotic syndrome (SRNS) have been identified. Our previous study found that mutations in nucleoporin 160 kD (NUP160) are implicated in SRNS. The NUP160 gene encodes a component of the nuclear pore complex. Recently, two siblings with homozygous NUP160 mutations presented with SRNS and a nervous system disorder. However, replication of nephrotic
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The role of alternative polyadenylation in epithelial-mesenchymal transition of non-small cell lung cancer Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-01-15 Sijia Wu, Xinyu Qin, Liyu Huang
The metastatic non-small cell lung cancer (NSCLC) is one of the cancers with high incidence, poor survival, and limited treatment. Epithelial-mesenchymal transition (EMT) is the first step by which an early tumor converts to an invasive one. Studying the underlying mechanisms of EMT can help the understanding of cancer metastasis and improve the treatment. In this study, 1013 NSCLC patients and 123
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Retention of stress susceptibility in the mdx mouse model of Duchenne muscular dystrophy after PGC-1α overexpression or ablation of IDO1 or CD38 Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-01-05 Erynn E Johnson, W Michael Southern, Baird Doud, Brandon Steiger, Maria Razzoli, Alessandro Bartolomucci, James M Ervasti
Duchenne muscular dystrophy (DMD) is a lethal degenerative muscle wasting disease caused by the loss of the structural protein dystrophin with secondary pathological manifestations including metabolic dysfunction, mood and behavioral disorders. In the mildly affected mdx mouse model of DMD, brief scruff stress causes inactivity, while more severe subordination stress results in lethality. Here, we
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Characterization of novel mutations in the TEL-patch domain of the telomeric factor TPP1 associated with telomere biology disorders Hum. Mol. Genet. (IF 3.5) Pub Date : 2024-01-02 Alexis Bertrand, Ibrahima Ba, Laëtitia Kermasson, Vithura Pirabakaran, Noémie Chable, Elodie Lainey, Christelle Ménard, Faten Kallel, Capucine Picard, Sondes Hadiji, Nathalie Coolen-Allou, Elodie Blanchard, Jean-Pierre de Villartay, Despina Moshous, Marie Roelens, Isabelle Callebaut, Caroline Kannengiesser, Patrick Revy
Telomeres are nucleoprotein structures that protect the chromosome ends from degradation and fusion. Telomerase is a ribonucleoprotein complex essential to maintain the length of telomeres. Germline defects that lead to short and/or dysfunctional telomeres cause telomere biology disorders (TBDs), a group of rare and heterogeneous Mendelian diseases including pulmonary fibrosis, dyskeratosis congenita
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Comprehensive whole-genome analyses of the UK Biobank reveal significant sex differences in both genotype missingness and allele frequency on the X chromosome Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-12-11 Desmond Zeya Chen, Delnaz Roshandel, Zhong Wang, Lei Sun, Andrew D Paterson
The UK Biobank is the most used dataset for genome-wide association studies (GWAS). GWAS of sex, essentially sex differences in minor allele frequencies (sdMAF), has identified autosomal SNPs with significant sdMAF, including in the UK Biobank, but the X chromosome was excluded. Our recent report identified multiple regions on the X chromosome with significant sdMAF, using short-read sequencing of
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Long term peripheral AAV9-SMN gene therapy promotes survival in a mouse model of spinal muscular atrophy Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-12-11 Aoife Reilly, Rebecca Yaworski, Ariane Beauvais, Bernard L Schneider, Rashmi Kothary
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by motor neuron loss and skeletal muscle atrophy. SMA is caused by the loss of the SMN1 gene and low SMN protein levels. Current SMA therapies work by increasing SMN protein in the body. Although SMA is regarded as a motor neuron disorder, growing evidence shows that several peripheral organs contribute to SMA
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Penetrance and expressivity of mitochondrial variants in a large clinically unselected population Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-21 Stuart J Cannon, Timothy Hall, Gareth Hawkes, Kevin Colclough, Roisin M Boggan, Caroline F Wright, Sarah J Pickett, Andrew T Hattersley, Michael N Weedon, Kashyap A Patel
Background: Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population. Method: Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881
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System-based integrated metabolomics and microRNA analysis identifies potential molecular alterations in human X-linked cerebral adrenoleukodystrophy brain. Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-17 Laila M Poisson,Navtej Kaur,Michelle M Felicella,Jaspreet Singh
X-linked adrenoleukodystrophy is a severe demyelinating neurodegenerative disease mainly affecting males. The severe cerebral adrenoleukodystrophy (cALD) phenotype has a poor prognosis and underlying mechanism of onset and progression of neuropathology remains poorly understood. In this study we aim to integrate metabolomic and microRNA (miRNA) datasets to identify variances associated with cALD. Postmortem
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Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-17 Brittany N Williams, Adam Draper, Patrick F Lang, Tylor R Lewis, Audrey L Smith, Steven J Mayerl, Marie Rougié, Jeremy M Simon, Vadim Y Arshavsky, Scott H Greenwald, David M Gamm, Isabel Pinilla, Benjamin D Philpot
Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) in humans cause retinitis pigmentosa (RP) with early macular involvement, albeit the disease progression varies widely due to genetic heterogeneity and IMPG2 mutation type. There are currently no treatments for IMPG2-RP. To aid preclinical studies toward eventual treatments, there is a need to better understand the progression
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Mitochondrial aminoacyl-tRNA synthetases trigger unique compensatory mechanisms in neurons Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-17 Oliver Podmanicky, Fei Gao, Benjamin Munro, Matthew J Jennings, Veronika Boczonadi, Denisa Hathazi, Juliane S Mueller, Rita Horvath
Mitochondrial aminoacyl-tRNA synthetase (mt-ARS) mutations cause severe, progressive, and often lethal diseases with highly heterogeneous and tissue-specific clinical manifestations. This study investigates the molecular mechanisms triggered by three different mt-ARS defects caused by biallelic mutations in AARS2, EARS2, and RARS2, using an in vitro model of human neuronal cells. We report distinct
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Epigenomic profiling of the infrapatellar fat pad in osteoarthritis Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-17 Peter Kreitmaier, Young-Chan Park, Diane Swift, Arthur Gilly, J Mark Wilkinson, Eleftheria Zeggini
Osteoarthritis is a prevalent, complex disease of the joints, and affects multiple intra-articular tissues. Here, we have examined genome-wide DNA methylation profiles of primary infrapatellar fat pad and matched blood samples from 70 osteoarthritis patients undergoing total knee replacement surgery. Comparing the DNA methylation profiles between these tissues reveal widespread epigenetic differences
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Subtyping and prognostic model construction based on vesicle-mediated transport-related genes in colorectal cancer Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-16 Wei Wu, Tong Huang, Shengwen Li, Guangwei Gong, Dan Zhao, Yue Qiu
Background Colorectal cancer (CRC) is impacted by various environmental and genetic variables. Dysregulation of vesicle-mediated transport-related genes (VMTRGs) has been observed in many malignancies, but their effect on prognosis in CRC remains unclear. Methods CRC samples were clustered into varying subtypes per differential expression of VMTRGs. R package was utilized to explore differences in
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Ovol2 promoter mutations in mice and human illuminate species-specific phenotypic divergence Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-16 Sweetu Susan Sunny, Jitka Lachova, Petr Kasparek, Marcela Palkova, Frantisek Spoutil, Jan Prochazka, Radislav Sedlacek, Petra Liskova, Zbynek Kozmik
Pathogenic variants in the highly conserved OVOL2 promoter region cause posterior polymorphous corneal dystrophy (PPCD) 1 by inducing an ectopic expression of the endothelial OVOL2 mRNA. Here we produced an allelic series of Ovol2 promoter mutations in the mouse model including the heterozygous c.-307T>C variant (RefSeq NM_021220.4) causing PPCD1 in humans. Despite the high evolutionary conservation
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Functional assay for assessment of pathogenicity of BAP1 variants Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-13 Pauliina E Repo, Michael P Backlund, Tero T Kivelä, Joni A Turunen
Background Pathogenic germline variants in BRCA1-Associated Protein 1 (BAP1) cause BAP1 tumor predisposition syndrome (BAP1-TPDS). Carriers run especially a risk of uveal (UM) and cutaneous melanoma, malignant mesothelioma, and clear cell renal carcinoma. Approximately half of increasingly reported BAP1 variants lack accurate classification. Correct interpretation of pathogenicity can improve prognosis
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Age- and region-dependent cortical excitability in the zQ175 Huntington disease mouse model Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-10 Yundi Wang, Daniel Ramandi, Marja D Sepers, James P Mackay, Lynn A Raymond
The neurodegenerative disorder, Huntington disease (HD), manifests as disorders of movement, cognition and mood. Although studies report abnormal corticostriatal synaptic function early in HD mouse models, less is known about cortical–cortical activity across brain regions and disease stages. Recently, we reported enhanced mesoscale spread of cortical responses to sensory stimulation in vivo at early-manifest
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A transcriptomics-based drug repositioning approach to identify drugs with similar activities for the treatment of muscle pathologies in spinal muscular atrophy (SMA) models. Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-10 Joseph M Hoolachan, Eve McCallion, Emma R Sutton, Özge Çetin, Paloma Pacheco-Torres, Maria Dimitriadi, Suat Sari, Gavin J Miller, Magnus Okoh, Lisa M Walter, Peter Claus, Matthew J A Wood, Daniel P Tonge, Melissa Bowerman
Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by the reduction of survival of motor neuron (SMN) protein levels. Although three SMN-augmentation therapies are clinically approved that significantly slow down disease progression, they are unfortunately not cures. Thus, complementary SMN-independent therapies that can target key SMA pathologies and that can support the clinically
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Clinical features, functional consequences, and rescue pharmacology of missense GRID1 and GRID2 human variants. Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-07 James P Allen,Kathryn B Garber,Riley Perszyk,Cara T Khayat,Steven A Kell,Maki Kaneko,Catherine Quindipan,Sulagna Saitta,Roger L Ladda,Stacy Hewson,Michal Inbar-Feigenberg,Chitra Prasad,Asuri N Prasad,Leah Olewiler,Weiyi Mu,Liana S Rosenthal,Marcello Scala,Pasquale Striano,Federico Zara,Tyler W McCullock,Robin-Tobias Jauss,Johannes R Lemke,David M MacLean,Cheng Zhu,Hongjie Yuan,Scott J Myers,Stephen
GRID1 and GRID2 encode the enigmatic GluD1 and GluD2 proteins, which form tetrameric receptors that play important roles in synapse organization and development of the central nervous system. Variation in these genes has been implicated in neurodevelopmental phenotypes. We evaluated GRID1 and GRID2 human variants from the literature, ClinVar, and clinical laboratories and found that many of these variants
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Pan-cancer scRNA-seq analysis reveals immunological and diagnostic significance of the peripheral blood mononuclear cells. Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-07 Yuanhang Zhang,Xiaorui Zhou,Yu Zhong,Xi Chen,Zeyu Li,Rui Li,Pengfei Qin,Shanshan Wang,Jianhua Yin,Shang Liu,Miaomiao Jiang,Qichao Yu,Yong Hou,Shiping Liu,Liang Wu
Peripheral blood mononuclear cells (PBMCs) reflect systemic immune response during cancer progression. However, a comprehensive understanding of the composition and function of PBMCs in cancer patients is lacking, and the potential of these features to assist cancer diagnosis is also unclear. Here, the compositional and status differences between cancer patients and healthy donors in PBMCs were investigated
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Whole genome sequencing of 4,787 individuals identifies gene-based rare variants in age-related macular degeneration Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-07 Alan Kwong, Matthew Zawistowski, Lars G Fritsche, Xiaowei Zhan, Jennifer Bragg-Gresham, Kari E Branham, Jayshree Advani, Mohammad Othman, Rinki Ratnapriya, Tanya M Teslovich, Dwight Stambolian, Emily Y Chew, Gonçalo R Abecasis, Anand Swaroop
Genome-wide association studies have contributed extensively to the discovery of disease-associated common variants. However, the genetic contribution to complex traits is still largely difficult to interpret. We report a genome-wide association study of 2394 cases and 2393 controls for age-related macular degeneration (AMD) via whole-genome sequencing, with 46.9 million genetic variants. Our study
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snRNA-seq analysis in multinucleated myogenic FSHD cells identifies heterogeneous FSHD transcriptome signatures associated with embryonic-like program activation and oxidative stress-induced apoptosis Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-07 Dongxu Zheng, Annelot Wondergem, Susan Kloet, Iris Willemsen, Judit Balog, Stephen J Tapscott, Ahmed Mahfouz, Anita van den Heuvel, Silvère M van der Maarel
The sporadic nature of DUX4 expression in FSHD muscle challenges comparative transcriptome analyses between FSHD and control samples. A variety of DUX4 and FSHD-associated transcriptional changes have been identified, but bulk RNA-seq strategies prohibit comprehensive analysis of their spatiotemporal relation, interdependence and role in the disease process. In this study, we used single-nucleus RNA-sequencing
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Two zebrafish cacna1s loss-of-function variants provide models of mild and severe CACNA1S-related myopathy Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-06 Yukari Endo, Linda Groom, Sabrina M Wang, Emanuela Pannia, Nigel W Griffiths, Jenica L M Van Gennip, Brian Ciruna, Jocelyn Laporte, Robert T Dirksen, James J Dowling
CACNA1S-related myopathy, due to pathogenic variants in the CACNA1S gene, is a recently described congenital muscle disease. Disease associated variants result in loss of gene expression and/or reduction of Cav1.1 protein stability. There is an incomplete understanding of the underlying disease pathomechanisms and no effective therapies are currently available. A barrier to the study of this myopathy
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Three linked variants have opposing regulatory effects on isovaleryl-CoA dehydrogenase gene expression Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-06 Elizabeth A Brown, Susan Kales, Michael James Boyle, Joseph Vitti, Dylan Kotliar, Steve Schaffner, Ryan Tewhey, Pardis C Sabeti
While genome-wide association studies (GWAS) and positive selection scans identify genomic loci driving human phenotypic diversity, functional validation is required to discover the variant(s) responsible. We dissected the IVD gene locus—which encodes the isovaleryl-CoA dehydrogenase enzyme—implicated by selection statistics, multiple GWAS, and clinical genetics as important to function and fitness
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Demonstration of the pathogenicity of a common non-exomic mutation in ABCA4 using iPSC-derived retinal organoids and retrospective clinical data Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-11-06 Erin R Burnight, Beau J Fenner, Ian C Han, Adam P DeLuca, S Scott Whitmore, Laura R Bohrer, Jeaneen L Andorf, Elliott H Sohn, Robert F Mullins, Budd A Tucker, Edwin M Stone
Mutations in ABCA4 are the most common cause of Mendelian retinal disease. Clinical evaluation of this gene is challenging because of its extreme allelic diversity, the large fraction of non-exomic mutations, and the wide range of associated disease. We used patient-derived retinal organoids as well as DNA samples and clinical data from a large cohort of patients with ABCA4-associated retinal disease
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A large-scale microRNA transcriptome-wide association study identifies two susceptibility microRNAs, miR-1307-5p and miR-192-3p, for colorectal cancer risk Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-30 Zhishan Chen, Weiqiang Lin, Qiuyin Cai, Sun-Seog Kweon, Xiao-Ou Shu, Chizu Tanikawa, Wei-Hua Jia, Ying Wang, Xinwan Su, Yuan Yuan, Wanqing Wen, Jeongseon Kim, Aesun Shin, Sun Ha Jee, Keitaro Matsuo, Dong-Hyun Kim, Nan Wang, Jie Ping, Min-Ho Shin, Zefang Ren, Jae Hwan Oh, Isao Oze, Yoon-Ok Ahn, Keum Ji Jung, Yu-Tang Gao, Zhi-Zhong Pan, Yoichiro Kamatani, Weidong Han, Jirong Long, Koichi Matsuda, Wei
Transcriptome-wide association studies (TWAS) have identified many putative susceptibility genes for colorectal cancer (CRC) risk. However, susceptibility miRNAs, critical dysregulators of gene expression, remain unexplored. We genotyped DNA samples from 313 CRC East Asian patients and performed small RNA sequencing in their normal colon tissues distant from tumors to build genetic models for predicting
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The progranulin cleavage product granulin 3 exerts a dominant negative effect on animal fitness Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-30 Austin L Wang, Edwina A Mambou, Aimee W Kao
Progranulin is an evolutionarily conserved protein that has been implicated in human neurodevelopmental and neurodegenerative diseases. Human progranulin is comprised of multiple cysteine-rich, biologically active granulin peptides. Granulin peptides accumulate with age and stress, however their functional contributions relative to full-length progranulin remain unclear. To address this, we generated
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The C-terminal extension of dyskerin is a dyskeratosis congenita mutational hotspot that modulates interaction with telomerase RNA and subcellular localization. Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-25 Jian Qin,Alexandre Garus,Chantal Autexier
Dyskerin is a component of the human telomerase complex and is involved in stabilizing the human telomerase RNA (hTR). Many mutations in the DKC1 gene encoding dyskerin are found in X-linked dyskeratosis congenita (X-DC), a premature aging disorder and other related diseases. The C-terminal extension (CTE) of dyskerin contributes to its interaction with the molecular chaperone SHQ1 during the early
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Morphological and functional alterations of neuromuscular synapses in a mouse model of ACTA1 congenital myopathy Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-25 Yun Liu, Weichun Lin
Mutations in skeletal muscle α-actin (Acta1) cause myopathies. In a mouse model of congenital myopathy, heterozygous Acta1 (H40Y) knock-in (Acta1+/Ki) mice exhibit features of human nemaline myopathy, including premature lethality, severe muscle weakness, reduced mobility, and the presence of nemaline rods in muscle fibers. In this study, we investigated the impact of Acta1 (H40Y) mutation on the neuromuscular
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Characterizing and predicting ccRCC-causing missense mutations in Von Hippel-Lindau disease Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-24 Adam Serghini, Stephanie Portelli, Guillaume Troadec, Catherine Song, Qisheng Pan, Douglas E V Pires, David B Ascher
Background: Mutations within the Von Hippel-Lindau (VHL) tumor suppressor gene are known to cause VHL disease, which is characterized by the formation of cysts and tumors in multiple organs of the body, particularly clear cell renal cell carcinoma (ccRCC). A major challenge in clinical practice is determining tumor risk from a given mutation in the VHL gene. Previous efforts have been hindered by limited
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Identification of conserved skeletal enhancers associated with craniosynostosis risk genes Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-24 Xuan Anita He (何璇), Anna Berenson, Michelle Bernard, Chris Weber, Laura Cook, Axel Visel, Juan I Fuxman Bass, Shannon Fisher
Craniosynostosis, defined by premature fusion of one or multiple cranial sutures, is a common congenital defect affecting more than 1/2000 infants and results in restricted brain expansion. Single gene mutations account for 15-20% of cases, largely as part of a syndrome, but the majority are nonsyndromic with complex underlying genetics. We hypothesized that the two noncoding genomic regions identified
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FSHD muscle shows perturbation in fibroadipogenic progenitor cells, mitochondrial function and alternative splicing independently of inflammation Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-19 Elise N Engquist, Anna Greco, Leo A B Joosten, Baziel G M van Engelen, Peter S Zammit, Christopher R S Banerji
Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy. FSHD is highly heterogeneous, with patients following a variety of clinical trajectories, complicating clinical trials. Skeletal muscle in FSHD undergoes fibrosis and fatty replacement that can be accelerated by inflammation, adding to heterogeneity. Well controlled molecular studies are thus essential to both categorise
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Memory decline, anxiety and depression in the mouse model of spinocerebellar ataxia type 3 Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-18 Ksenia S Marinina, Ilya B Bezprozvanny, Polina A Egorova
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant hereditary disorder, caused by an expansion of polyglutamine in the ataxin-3 protein. SCA3 symptoms include progressive motor decline caused by an atrophy of the cerebellum and brainstem. However, it was recently reported that SCA3 patients also suffer from the cerebellar cognitive affective syndrome. The majority of SCA3 patients exhibit
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Novel insight into the etiology of ischemic stroke gained by integrative multiome-wide association study Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-12 Junghyun Jung, Zeyun Lu, Adam Smith, Nicholas Mancuso
Stroke, characterized by sudden neurological deficits, is the second leading cause of death worldwide. Although genome-wide association studies (GWAS) have successfully identified many genomic regions associated with ischemic stroke (IS), the genes underlying risk and their regulatory mechanisms remain elusive. Here, we integrate a large-scale GWAS (N = 1 296 908) for IS together with molecular QTLs
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Comparison of pharmaceutical properties and biological activity of prednisolone, deflazacort, and vamorolone in DMD disease models Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-11 Grace Liu, Philip Lipari, Anna Mollin, Stephen Jung, Irina Teplova, Wencheng Li, Lanqing Ying, Vijay More, William Lennox, Shirley Yeh, Eric McGann, Young-Choon Moon, Cari Rice, Eduardo Huarte, Barbara Gruszka, Balmiki Ray, Elizabeth Goodwin, Patricia Buckendahl, Edward Yurkow, Bruce Braughton, Jana Narasimhan, Ellen Welch, Gregory Voronin, Marla Weetall
Duchenne muscular dystrophy (DMD) is a progressive disabling X-linked recessive disorder that causes gradual and irreversible loss of muscle, resulting in early death. The corticosteroids prednisone/prednisolone and deflazacort are used to treat DMD as the standard of care; however, only deflazacort is FDA approved for DMD. The novel atypical corticosteroid vamorolone is being investigated for treatment
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Functional analysis of germline VANGL2 variants using rescue assays of vangl2 knockout zebrafish Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-10 Christopher J Derrick, Emmanuelle Szenker-Ravi, Adrian Santos-Ledo, Ahlam Alqahtani, Amirah Yusof, Lorraine Eley, Alistair H L Coleman, Sumanty Tohari, Alvin Yu-Jin Ng, Byrappa Venkatesh, Essa Alharby, Luke Mansard, Marie-Noelle Bonnet-Dupeyron, Anne-Francoise Roux, Christel Vaché, Joëlle Roume, Patrice Bouvagnet, Naif A M Almontashiri, Deborah J Henderson, Bruno Reversade, Bill Chaudhry
Developmental studies have shown that the evolutionarily conserved Wnt planar cell polarity (PCP) pathway is essential for the development of a diverse range of tissues and organs including the brain, spinal cord, heart and sensory organs as well as establishment of the left–right body axis. Germline mutations in the highly conserved PCP gene VANGL2 in humans have only been associated with central
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CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-10 Mario K Shammas, Yu Nie, Alexandra Gilsrud, Xiaoping Huang, Derek P Narendra, Patrick F Chinnery
Mutations affecting the mitochondrial intermembrane space protein CHCHD10 cause human disease, but it is not known why different amino acid substitutions cause markedly different clinical phenotypes, including amyotrophic lateral sclerosis-frontotemporal dementia, spinal muscular atrophy Jokela-type, isolated autosomal dominant mitochondrial myopathy and cardiomyopathy. CHCHD10 mutations have been
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Correction to: The potential of utrophin and dystrophin combination therapies for Duchenne muscular dystrophy. Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-04
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Correction to: Myofibrillar myopathy hallmarks associated with ZAK deficiency. Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-03
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CYP2A6 associates with respiratory disease risk and younger age of diagnosis: a phenome-wide association Mendelian randomization study Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-03 Haidy Giratallah, Meghan J Chenoweth, Jennie G Pouget, Ahmed El-Boraie, Alaa Alsaafin, Caryn Lerman, Jo Knight, Rachel F Tyndale
CYP2A6, a genetically variable enzyme, inactivates nicotine, activates carcinogens, and metabolizes many pharmaceuticals. Variation in CYP2A6 influences smoking behaviours and tobacco-related disease risk. This phenome-wide association study examined associations between a reconstructed version of our weighted genetic risk score (wGRS) for CYP2A6 activity with diseases in the UK Biobank (N = 395 887)
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Dysregulation of alternative splicing in spinocerebellar ataxia type 1 Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-03 Victor Olmos, Evrett Thompson, Neha Gogia, Kimberly Luttik, Vaishnavi Veeranki, Luhan Ni, Serena Sim, Kelly Chen, Diane S Krause, Janghoo Lim
Spinocerebellar ataxia type 1 is caused by an expansion of the polyglutamine tract in ATAXIN-1. Ataxin-1 is broadly expressed throughout the brain and is involved in regulating gene expression. However, it is not yet known if mutant ataxin-1 can impact the regulation of alternative splicing events. We performed bulk RNA sequencing in mouse models of spinocerebellar ataxia type 1 and identified that
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Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-10-02 Hidehiro Suginobe, Hidekazu Ishida, Yoichiro Ishii, Kazutoshi Ueda, Chika Yoshihara, Atsuko Ueyama, Renjie Wang, Hirofumi Tsuru, Kazuhisa Hashimoto, Masaki Hirose, Ryo Ishii, Jun Narita, Yasuji Kitabatake, Keiichi Ozono
Down syndrome (DS) is the most prevalent chromosomal disorder associated with a higher incidence of pulmonary arterial hypertension (PAH). The dysfunction of vascular endothelial cells (ECs) is known to cause pulmonary arterial remodeling in PAH, although the physiological characteristics of ECs harboring trisomy 21 (T21) are still unknown. In this study, we analyzed the human vascular ECs by utilizing
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Multi-omics analysis reveals the potential pathogenesis and therapeutic targets of diabetic kidney disease Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-09-29 Lan Wei, Jingjing Gao, Liangzhi Wang, Qianru Tao, Chao Tu
Clinicians have long been interested in understanding the molecular basis of diabetic kidney disease (DKD)and its potential treatment targets. Its pathophysiology involves protein phosphorylation, one of the most recognizable post-transcriptional modifications, that can take part in many cellular functions and control different metabolic processes. In order to recognize the molecular and protein changes
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Translation reinitiation in c.453delC frameshift mutation of KCNH2 producing functional hERG K+ channels with mild dominant negative effect in the heterozygote patient-derived iPSC cardiomyocytes Hum. Mol. Genet. (IF 3.5) Pub Date : 2023-09-27 Na Kyeong Park, Soon-Jung Park, Yun-Gwi Park, Sung-Hwan Moon, JooHan Woo, Hyun Jong Kim, Sung Joon Kim, Seong Woo Choi
Background The c.453delC (p.Thr152Profs*14) frameshift mutation in KCNH2 is associated with an elevated risk of Long QT syndrome (LQTS) and fatal arrhythmia. Nevertheless, the loss-of-function mechanism underlying this mutation remains unexplored and necessitates an understanding of electrophysiology. Methods To gain insight into the mechanism of the LQT phenotype, we conducted whole-cell patch-clamp