journal
https://read.qxmd.com/read/38340007/muscle-eosinophilia-is-a-hallmark-of-chronic-disease-in-facioscapulohumeral-muscular-dystrophy
#21
JOURNAL ARTICLE
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 mechanisms are still unclear. Histologically, FSHD affected muscles show a characteristic dystrophic phenotype that is often accompanied by a pronounced immune cell infiltration, but the role of the immune system in FSHD is not understood...
February 10, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38339995/the-genetic-dissection-of-fetal-haemoglobin-persistence-in-sickle-cell-disease-in-nigeria
#22
JOURNAL ARTICLE
Oyesola O Ojewunmi, Titilope A Adeyemo, Ajoke I Oyetunji, Bassey Inyang, Afolashade Akinrindoye, Baraka S Mkumbe, Kate Gardner, Helen Rooks, John Brewin, Hamel Patel, Sang Hyuck Lee, Raymond Chung, Sara Rashkin, Guolian Kang, Reuben Chianumba, Raphael Sangeda, Liberata Mwita, Hezekiah Isa, Uche-Nnebe Agumadu, Rosemary Ekong, Jamilu A Faruk, Bello Y Jamoh, Niyi M Adebiyi, Ismail A Umar, Abdulaziz Hassan, Christopher Grace, Anuj Goel, Baba P D Inusa, Mario Falchi, Siana Nkya, Julie Makani, Hafsat R Ahmad, Obiageli Nnodu, John Strouboulis, Stephan Menzel
The clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A, HBS1L-MYB, and Xmn1-HBG2) have been reported, but a considerable hidden heritability remains. We conducted a genome-wide association study for HbF levels in 1006 Nigerian patients with SCD (HbSS/HbSβ0), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients). To dissect association signals at the major loci, we performed stepwise conditional and haplotype association analyses and included public functional annotation datasets...
February 10, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38324746/pathways-controlling-neurotoxicity-and-proteostasis-in-mitochondrial-complex-i-deficiency
#23
JOURNAL ARTICLE
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 retina to probe the role of protein degradation abnormalities in mitochondrial encephalomyopathies. Using our genetic model, we found that complex I deficiency regulates both the ubiquitin/proteasome and autophagy/lysosome arms of the proteostasis machinery...
February 7, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38311346/splicing-analysis-of-24-potential-spliceogenic-variants-in-mmr-genes-and-clinical-interpretation-based-on-refined-acmg-amp-criteria
#24
JOURNAL ARTICLE
Ahmed Bouras, Cedrick Lefol, Eric Ruano, Chloé Grand-Masson, Jessie Auclair-Perrossier, Qing Wang
Lynch syndrome (LS) is a common hereditary cancer syndrome caused by heterozygous germline pathogenic variants in DNA mismatch repair (MMR) genes. Splicing defect constitutes one of the major mechanisms for MMR gene inactivation. Using RT-PCR based RNA analysis, we investigated 24 potential spliceogenic variants in MMR genes and determined their pathogenicity based on refined splicing-related American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. Aberrant transcripts were confirmed in 19 variants and 17 of which were classified as pathogenic including 11 located outside of canonical splice sites...
February 4, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38297980/excessive-tubulin-glutamylation-leads-to-progressive-cone-rod-dystrophy-and-loss-of-outer-segment-integrity
#25
JOURNAL ARTICLE
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. The observed functional reduction was not due to cell death, levels, or the mislocalization of major phototransduction proteins...
January 31, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38280232/opa1-mutation-affects-autophagy-and-triggers-senescence-in-autosomal-dominant-optic-atrophy-plus-fibroblasts
#26
JOURNAL ARTICLE
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 focused on fibroblasts from a patient with Autosomal Dominant Optic Atrophy (ADOA) plus syndrome harboring a mutation in the Optic Atrophy 1 (OPA1) gene...
January 27, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38280230/mitochondrial-protein-synthesis-quality-control
#27
JOURNAL ARTICLE
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 that require co-translational insertion into the inner membrane of the organelle. To maintain the integrity of the inner membrane, which is essential for organelle function, requires responsive quality control mechanisms to recognize aberrations in protein synthesis...
January 27, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38280229/deletion-of-a-conserved-genomic-region-associated-with-adolescent-idiopathic-scoliosis-leads-to-vertebral-rotation-in-mice
#28
JOURNAL ARTICLE
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 function of a highly conserved genomic region previously linked to AIS using a mouse model generated by CRISPR-CAS9 gene editing to knockout this area of the genome to understand better its contribution to AIS, which we named AIS_CRMΔ...
January 27, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38272461/removal-of-pomt1-in-zebrafish-leads-to-loss-of-%C3%AE-dystroglycan-glycosylation-and-dystroglycanopathy-phenotypes
#29
JOURNAL ARTICLE
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). Disruptions in these cell-ECM interactions lead to multiple developmental defects causing brain and eye malformations in addition to CMD...
January 25, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38272457/high-throughput-functional-profiling-of-genes-at-intraocular-pressure-loci-reveals-distinct-networks-for-glaucoma
#30
JOURNAL ARTICLE
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 variation that can be attributed to trabecular meshwork cell (TMC) dysfunction and raised IOP in POAG...
January 25, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38271184/challenges-and-approaches-to-calibrating-patient-phenotype-as-evidence-for-cancer-gene-variant-classification-under-acmg-amp-guidelines
#31
JOURNAL ARTICLE
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 patient presentation as evidence towards pathogenicity. Application of PS4 can be done through traditional case-control studies, or "proband counting" within or across clinical testing cohorts...
January 25, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38271183/spint2-mutations-in-the-kunitz-domain-2-found-in-scsd-patients-inactivate-hai-2-as-prostasin-inhibitor-via-abnormal-protein-folding-and-n-glycosylation
#32
JOURNAL ARTICLE
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 affect the functionally less important Kunitz domain 2. How theses single amino acid substitutions inactivate HAI-2 was, here, investigated by the doxycycline-inducible expression of three of these mutants in HAI-2-knockout Caco-2 human colorectal adenocarcinoma cells...
January 25, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38268317/regional-and-bilateral-mri-and-gene-signatures-in-facioscapulohumeral-dystrophy-implications-for-clinical-trial-design-and-mechanisms-of-disease-progression
#33
JOURNAL ARTICLE
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 in the mid-portion of the tibialis anterior (TA) muscles bilaterally in FSHD subjects and validated our prior reports of the strong association between MRI characteristics and expression of genes regulated by DUX4 and other gene categories associated with FSHD disease activity...
January 24, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38263910/novel-breast-cancer-susceptibility-loci-under-linkage-peaks-identified-in-african-ancestry-consortia
#34
JOURNAL ARTICLE
Heather M Ochs-Balcom, Leah Preus, Zhaohui Du, Robert C Elston, Craig C Teerlink, Guochong Jia, Xingyi Guo, Qiuyin Cai, Jirong Long, Jie Ping, Bingshan Li, Daniel O Stram, Xiao-Ou Shu, Maureen Sanderson, Guimin Gao, Thomas Ahearn, Kathryn L Lunetta, Gary Zirpoli, Melissa A Troester, Edward A Ruiz-Narváez, Stephen A Haddad, Jonine Figueroa, Esther M John, Leslie Bernstein, Jennifer J Hu, Regina G Ziegler, Sarah Nyante, Elisa V Bandera, Sue A Ingles, Nicholas Mancuso, Michael F Press, Sandra L Deming, Jorge L Rodriguez-Gil, Song Yao, Temidayo O Ogundiran, Oladosu Ojengbede, Manjeet K Bolla, Joe Dennis, Alison M Dunning, Douglas F Easton, Kyriaki Michailidou, Paul D P Pharoah, Dale P Sandler, Jack A Taylor, Qin Wang, Katie M O'Brien, Clarice R Weinberg, Cari M Kitahara, William Blot, Katherine L Nathanson, Anselm Hennis, Barbara Nemesure, Stefan Ambs, Lara E Sucheston-Campbell, Jeannette T Bensen, Stephen J Chanock, Andrew F Olshan, Christine B Ambrosone, Olufunmilayo I Olopade, David V Conti, Julie Palmer, Montserrat García-Closas, Dezheng Huo, Wei Zheng, Christopher Haiman
BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls...
January 23, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38224683/podocyte-specific-nup160-knockout-mice-develop-nephrotic-syndrome-and-glomerulosclerosis
#35
JOURNAL ARTICLE
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 syndrome (NS)-associated phenotypes in a mammalian model following loss of Nup160 is needed to prove that NUP160 mutations cause SRNS...
January 15, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38224682/the-role-of-alternative-polyadenylation-in-epithelial-mesenchymal-transition-of-non-small-cell-lung-cancer
#36
JOURNAL ARTICLE
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 NSCLC cell lines are deeply analyzed for the potential roles of alternative polyadenylation (APA) in the EMT process...
January 15, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38217426/correction-to-heterogeneity-in-the-progression-of-retinal-pathologies-in-mice-harboring-patient-mimicking-impg2-mutations
#37
(no author information available yet)
No abstract text is available yet for this article.
January 13, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38215789/identifying-bmi-associated-genes-via-a-genome-wide-multi-omics-integrative-approach-using-summary-data
#38
JOURNAL ARTICLE
Jingxian Tang, Hanfei Xu, Zihao Xin, Quanshun Mei, Musong Gao, Tiantian Yang, Xiaoyu Zhang, Daniel Levy, Ching-Ti Liu
OBJECTIVE: This study aims to identify BMI-associated genes by integrating aggregated summary information from different omics data. METHODS: We conducted a meta-analysis to leverage information from a genome-wide association study (n = 339 224), a transcriptome-wide association study (n = 5619), and an epigenome-wide association study (n = 3743). We prioritized the significant genes with a machine learning-based method, netWAS, which borrows information from adipose tissue-specific interaction networks...
January 12, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38181046/retention-of-stress-susceptibility-in-the-mdx-mouse-model-of-duchenne-muscular-dystrophy-after-pgc-1%C3%AE-overexpression-or-ablation-of-ido1-or-cd38
#39
JOURNAL ARTICLE
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 investigated the kynurenine pathway of tryptophan degradation and the nicotinamide adenine dinucleotide (NAD+) metabolic pathway in mdx mice and their involvement as possible mediators of mdx stress-related pathology...
January 5, 2024: Human Molecular Genetics
https://read.qxmd.com/read/38176734/characterization-of-novel-mutations-in-the-tel-patch-domain-of-the-telomeric-factor-tpp1-associated-with-telomere-biology-disorders
#40
JOURNAL ARTICLE
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, and Høyeraal-Hreidarsson syndrome. TPP1, a telomeric factor encoded by the gene ACD, recruits telomerase at telomere and stimulates its activity via its TEL-patch domain that directly interacts with TERT, the catalytic subunit of telomerase...
January 4, 2024: Human Molecular Genetics
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