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MSH2 knock-down shows CTG repeat stability and concomitant upstream demethylation at the DMPK locus in myotonic dystrophy type 1 human embryonic stem cells Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-11-26 Franck S, Barbé L, Ardui S, et al.
AbstractMyotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the DMPK gene, where expansion size and somatic mosaicism correlates with disease severity and age of onset. While it is known that the mismatch repair protein MSH2 contributes to the unstable nature of the repeat, its role on other disease-related features, such as CpG methylation upstream of the repeat, is unknown.
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Evolutionary history of sickle cell mutation: implications for global genetic medicine Hum. Mol. Genet. (IF 5.1) Pub Date : 2021-01-18 Kevin Esoh; Ambroise Wonkam
Resistance afforded by the sickle-cell trait against severe malaria has led to high frequencies of the sickle-cell mutation [HBB; c.20 T > A, p.Glu6Val; OMIM: 141900 (HBB-βS)] in most parts of Africa. High-coverage sequencing and genotype data have now confirmed the single African origin of the sickle-cell gene variant [HBB; c.20 T > A, p.Glu6Val; OMIM: 141900 (HBB-βS)]. Nevertheless, the classical
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When is an obscurin variant pathogenic? The impact of Arg4344Gln and Arg4444Trp variants on protein–protein interactions and protein stability Hum. Mol. Genet. (IF 5.1) Pub Date : 2021-01-12 Atsushi Fukuzawa; Daniel Koch; Sarah Grover; Martin Rees; Mathias Gautel
Obscurin is a giant muscle protein that connects the sarcomere with the sarcoplasmic reticulum, with poorly understood structural and signalling functions. Increasingly, obscurin variants are implicated in the pathophysiology of cardiovascular diseases. The Arg4344Gln variant (R4344Q) in obscurin domain Ig58, initially discovered in a patient with hypertrophic cardiomyopathy, has been reported to impair
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Evolutionary genetics of skin pigmentation in African populations Hum. Mol. Genet. (IF 5.1) Pub Date : 2021-01-12 Yuanqing Feng; Michael A McQuillan; Sarah A Tishkoff
Skin color is a highly heritable human trait, and global variation in skin pigmentation has been shaped by natural selection, migration, and admixture. Ethnically diverse African populations harbor extremely high levels of genetic and phenotypic diversity, and skin pigmentation varies widely across Africa. Recent genome-wide genetic studies of skin pigmentation in African populations have advanced
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Glutathione S-transferase Pi (Gstp) Proteins Regulate Neuritogenesis in the Developing Cerebral Cortex Hum. Mol. Genet. (IF 5.1) Pub Date : 2021-01-12 Xiaonan Liu; Sara M Blazejewski; Sarah A Bennison; Kazuhito Toyo-oka
GSTP proteins are metabolic enzymes involved in removal of oxidative stress and intracellular signaling and also have inhibitory effects on JNK activity. However, the functions of Gstp proteins in the developing brain are unknown. In mice, there are three Gstp proteins, Gstp1, 2 and 3, while there is only one GSTP in humans. By RT-PCR analysis, we found that Gstp1 was expressed beginning at E15.5 in
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Single cell ATAC-Seq reveals cell type-specific transcriptional regulation and unique chromatin accessibility in human spermatogenesis Hum. Mol. Genet. (IF 5.1) Pub Date : 2021-01-12 Xiaolong Wu; Mujun Lu; Damin Yun; Sheng Gao; Shitao Chen; Longfei Hu; Yunhao Wu; Xiaorong Wang; Enkui Duan; C Yan Cheng; Fei Sun
During human spermatogenesis, germ cells undergo dynamic changes in chromatin organization/re-packaging and in transcriptomes. In order to better understand the underlying mechanism(s), scATAC-Seq of 5376 testicular cells from 3 normal men were performed. Data were analyzed in parallel with the scRNA-Seq data of human testicular cells. Ten germ cell types associated with spermatogenesis and 6 testicular
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The Sub-Saharan African information potential to unveil adaptations to infectious diseases Hum. Mol. Genet. (IF 5.1) Pub Date : 2021-01-12 Nicole Pedro; Ricardo J Pinto; Bruno Cavadas; Luisa Pereira
Sub-Saharan Africa is the most promising region of the world to conduct high-throughput studies to unveil adaptations to infectious diseases due to several reasons, namely: the longest evolving time-depth in the Homo sapiens phylogenetic tree (at least 2/3 older than any other worldwide region); the continuous burden of infectious diseases (still number one in health/life threat); and the coexistence
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Heritability and family-based GWAS analyses of the N-acyl ethanolamine and ceramide plasma lipidome Hum. Mol. Genet. (IF 5.1) Pub Date : 2021-01-12 Kathryn A McGurk; Simon G Williams; Hui Guo; Hugh Watkins; Martin Farrall; Heather J Cordell; Anna Nicolaou; Bernard D Keavney
Signalling lipids of the N-acyl ethanolamine (NAE) and ceramide (CER) classes have emerged as potential biomarkers of cardiovascular disease (CVD). We sought to establish the heritability of plasma NAEs (including the endocannabinoid anandamide) and CERs, to identify common DNA variants influencing the circulating concentrations of the heritable lipids, and assess causality of these lipids in CVD using
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Dimethyl fumarate dose-dependently increases mitochondrial gene expression and function in muscle and brain of Friedreich’s ataxia model mice Hum. Mol. Genet. (IF 5.1) Pub Date : 2021-01-11 Chun Kiu Hui; Elena N Dedkova; Claire Montgomery; Gino Cortopassi
Previously we showed that Dimethyl fumarate (DMF) dose-dependently increased mitochondrial gene expression and function in cells and might be considered as a therapeutic for inherited mitochondrial disease, including Friedreich’s ataxia. Here we tested DMF’s ability to dose-dependently increase mitochondrial function, mitochondrial gene expression (frataxin and cytochrome oxidase protein) and mitochondrial
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Mutations causing Lopes-Maciel-Rodan Syndrome are huntingtin hypomorphs Hum. Mol. Genet. (IF 5.1) Pub Date : 2021-01-11 Roy Jung; Yejin Lee; Douglas Barker; Kevin Correia; Baehyun Shin; Jacob Loupe; Ryan L Collins; Diane Lucente; Jayla Ruliera; Tammy Gillis; Jayalakshmi S Mysore; Lance Rodan; Jonathan Picker; Jong-Min Lee; David Howland; Ramee Lee; Seung Kwak; Marcy E MacDonald; James F Gusella; Ihn Sik Seong
Huntington’s disease (HD) pathogenesis involves a genetic gain-of-function toxicity mechanism triggered by the expanded HTT CAG repeat. Current therapeutic efforts aim to suppress expression of total or mutant huntingtin, though the relationship of huntingtin’s normal activities to the gain-of-function mechanism and what the effects of huntingtin-lowering might be are unclear. Here, we have re-investigated
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Loss of sarcospan exacerbates pathology in mdx mice, but does not affect utrophin amelioration of disease Hum. Mol. Genet. (IF 5.1) Pub Date : 2021-01-11 Elizabeth M Gibbs; Jackie L McCourt; Kara M Shin; Katherine G Hammond; Jamie L Marshall; Rachelle H Crosbie
The dystrophin-glycoprotein complex (DGC) is a membrane adhesion complex that provides structural stability at the sarcolemma by linking the myocyte’s internal cytoskeleton and external extracellular matrix. In Duchenne muscular dystrophy (DMD), the absence of dystrophin leads to the loss of the DGC at the sarcolemma, resulting in sarcolemmal instability and progressive muscle damage. Utrophin, an
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Loss of FEZ1, a gene deleted in Jacobsen syndrome, causes locomotion defects and early mortality by impairing motor neuron development Hum. Mol. Genet. (IF 5.1) Pub Date : 2021-01-04 Saravanan Gunaseelan; Ziyin Wang; Venetia Kok Jing Tong; Sylvester Wong Shu Ming; Rafhanah Banu Bte Abdul Razar; Sumitra Srimasorn; Wei-Yi Ong; Kah-Leong Lim; John Jia En Chua
FEZ1-mediated axonal transport plays important roles in central nervous system development but its involvement in the peripheral nervous system is not well-characterised. FEZ1 is deleted in Jacobsen syndrome (JS), an 11q terminal deletion developmental disorder. JS patients display impaired psychomotor skills, including gross and fine motor delay, suggesting that FEZ1 deletion may be responsible for
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Pulmonary glycogen deficiency as a new potential cause of respiratory distress syndrome Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-11-20 Testoni G, Olmeda B, Duran J, et al.
AbstractThe glycogenin knockout mouse is a model of Glycogen Storage Disease type XV. These animals show high perinatal mortality (90%) due to respiratory failure. The lungs of glycogenin-deficient embryos and P0 mice have a lower glycogen content than that of wild-type counterparts. Embryonic lungs were found to have decreased levels of mature surfactant proteins SP-B and SP-C, together with incomplete
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Neuroligin dependence of social behaviour in Caenorhabditis elegans provides a model to investigate an autism-associated gene Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-11-18 Helena Rawsthorne; Fernando Calahorro; Emily Feist; Lindy Holden-Dye; Vincent O’Connor; James Dillon
Autism spectrum disorder (ASD) is characterized by a triad of behavioural impairments including social behaviour. Neuroligin, a trans-synaptic adhesion molecule, has emerged as a penetrant genetic determinant of behavioural traits that signature the neuroatypical behaviours of autism. However, the function of neuroligin in social circuitry and the impact of genetic variation to this gene is not fully
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Ryanodine receptor remodeling in cardiomyopathy and muscular dystrophy caused by lamin A/C gene mutation Hum. Mol. Genet. (IF 5.1) Pub Date : 2021-01-04 Haikel Dridi; Wei Wu; Steven R Reiken; Rachel M Ofer; Yang Liu; Qi Yuan; Leah Sittenfeld; Jared Kushner; Antoine Muchir; Howard J Worman; Andrew R Marks
Mutations in the lamin A/C gene (LMNA), which encodes A-type lamins, cause several diseases called laminopathies, the most common of which is dilated cardiomyopathy with muscular dystrophy. The role of Ca2+ regulation in these diseases remain poorly understood. We now show biochemical remodeling of the ryanodine receptor (RyR)/intracellular Ca2+ release channel in heart samples from human subjects
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Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-12-31 Amrutha Pattamatta; Lien Nguyen; Hailey R Olafson; Marina M Scotti; Lauren A Laboissonniere; Jared Richardson; J Andrew Berglund; Tao Zu; Eric. T Wang; Laura P W Ranum
C9orf72 ALS/FTD patients show remarkable clinical heterogeneity, but the complex biology of the repeat expansion mutation has limited our understanding of the disease. BAC transgenic mice were used to better understand the molecular mechanisms and repeat length effects of C9orf72 ALS/FTD. Genetic analyses of these mice demonstrate that the BAC transgene and not integration site effects cause ALS/FTD
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Corrigendum to: Genome-wide heritability analysis of severe malaria resistance reveals evidence of polygenic inheritance Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-11-06 Damena D, Chimusa E.
In the original article, there were several inaccuracies noted and listed in this corrigendum.
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RPGR isoform imbalance causes ciliary defects due to exon ORF15 mutations in X-linked retinitis pigmentosa (XLRP) Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-12-23 Laura Moreno-Leon; Emma L West; Michelle O’Hara-Wright; Linjing Li; Rohini Nair; Jie He; Manisha Anand; Bhubanananda Sahu; Venkat Ramana Murthy Chavali; Alexander J Smith; Robin R Ali; Samuel G Jacobson; Artur V Cideciyan; Hemant Khanna
Mutations in RPGR (retinitis pigmentosa GTPase regulator) cause severe retinal ciliopathy, X-linked retinitis pigmentosa. Although two major alternatively spliced isoforms, RPGRex1-19 and RPGRORF15 are expressed, the relative importance of these isoforms in disease pathogenesis is unclear. Here, we analyzed fibroblast samples from eight patients and found that all of them form longer cilia than normal
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Kisspeptin deficiency leads to abnormal adrenal glands and excess steroid hormone secretion Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-21 Annabel Berthon; Nikolaos Settas; Angela Delaney; Andreas Giannakou; Andrew Demidowich; Fabio R Faucz; Stephanie B Seminara; Margaret E Chen; Constantine A Stratakis
Knockout mice for the kisspeptin receptor, Kiss1r (Kiss1r−/−) and its ligand kisspeptin, Kiss1 (Kiss1−/−) replicate the phenotype of isolated hypogonadotropic hypogonadism (IHH) associated with variants of these genes in humans. A recent report suggests that kisspeptin may be involved in human fetal adrenocortical development and function. Herein, we characterized the adrenal function and morphology
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Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-19 Wesley R Sun; Sara Ramirez; Kelly E Spiller; Yan Zhao; Sabine Fuhrmann
Uveal coloboma represents one of the most common congenital ocular malformations accounting for up to 10% of childhood blindness (~1 in 5000 live birth). Coloboma originates from defective fusion of the optic fissure (OF), a transient gap that forms during eye morphogenesis by asymmetric, ventral invagination. Genetic heterogeneity combined with the activity of developmentally regulated genes suggests
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Unravelling the disease mechanism for TSPYL1 deficiency Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-19 Gunnar Buyse; Michela Di Michele; Anouck Wijgaerts; Sophie Louwette; Christine Wittevrongel; Chantal Thys; Kate Downes; Berten Ceulemans; Hild Van Esch; Chris Van Geet; Kathleen Freson
We describe a lethal combined nervous and reproductive systems disease in three affected siblings of a consanguineous family. The phenotype was characterized by visceroautonomic dysfunction (neonatal bradycardia/apnea, feeding problems, hyperactive startle reflex), severe postnatal progressive neurological abnormalities (including abnormal neonatal cry, hypotonia, epilepsy, polyneuropathy, cerebral
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SWI/SNF inactivation in the endometrial epithelium leads to loss of epithelial integrity Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-19 Jake J Reske; Mike R Wilson; Jeanne Holladay; Marc Wegener; Marie Adams; Ronald L Chandler
Although ARID1A mutations are a hallmark feature, mutations in other SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling subunits are also observed in endometrial neoplasms. Here, we interrogated the roles of Brahma/SWI2-related gene 1 (BRG1, SMARCA4), the SWI/SNF catalytic subunit, in the endometrial epithelium. BRG1 loss affects more than one-third of all active genes and highly overlaps
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Variants in RABL2A causing male infertility and ciliopathy Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-19 Xinbao Ding; Robert Fragoza; Priti Singh; Shu Zhang; Haiyuan Yu; John C Schimenti
Approximately 7% of men worldwide suffer from infertility, with sperm abnormalities being the most common defect. Though genetic causes are thought to underlie a substantial fraction of idiopathic cases, the actual molecular bases are usually undetermined. Because the consequences of most genetic variants in populations are unknown, this complicates genetic diagnosis even after genome sequencing of
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De novo variants in MPP5 cause global developmental delay and behavioral changes Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-19 Noelle Sterling; Anna R Duncan; Raehee Park; David A Koolen; Jiahai Shi; Seo-Hee Cho; Paul J Benke; Patricia E Grant; Casie A Genetti; Grace E VanNoy; Jane Juusola; Kirsty McWalter; Jillian S Parboosingh; Ryan E Lamont; Francois P Bernier; Christopher Smith; David J Harris; Alexander P A Stegmann; A Micheil Innes; Seonhee Kim; Pankaj B Agrawal
Membrane Protein Palmitoylated 5 (MPP5) is a highly conserved apical complex protein essential for cell polarity, fate and survival. Defects in cell polarity are associated with neurologic disorders including autism and microcephaly. MPP5 is essential for neurogenesis in animal models, but human variants leading to neurologic impairment have not been described. We identified three patients with heterozygous
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Cancer (Epi)Genomics Comes of Age Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-20 Eng C, Plass C.
“Faith and science, I have learned, are two sides of the same coin, separated by an expanse so small but so wide that one side can’t see the other. They don’t know how they are connected.” – Mary E. Pearson (The Adoration of Jenna Fox)
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NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-26 Harikiran Nistala; John Dronzek; Claudia Gonzaga-Jauregui; Shek Man Chim; Saathyaki Rajamani; Samer Nuwayhid; Dennis Delgado; Elizabeth Burke; Ender Karaca; Matthew C Franklin; Prasad Sarangapani; Michael Podgorski; Yajun Tang; Melissa G Dominguez; Marjorie Withers; Ron A Deckelbaum; Christopher J Scheonherr; William A Gahl; May C Malicdan; Brian Zambrowicz; Nicholas W Gale; Richard A Gibbs; Wendy
Neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is
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MN1 overexpression with varying tumor grade is a promising predictor of survival of glioma patients Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-26 Saini M, Jha A, Tangri R, et al.
AbstractGliomas have substantial mortality to incidence rate ratio and a dismal clinical course. Newer molecular insights, therefore, are imperative to refine glioma diagnosis, prognosis and therapy. Meningioma 1 (MN1) gene is a transcriptional co-regulator implicated in other malignancies, albeit its significance in glioma pathology remains to be explored. IGFBP5 is regulated transcriptionally by
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The prevalent I686T human variant and loss-of-function mutations in the cardiomyocyte-specific kinase gene TNNI3K cause adverse contractility and concentric remodeling in mice Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-21 Peiheng Gan; Catalin Baicu; Hirofumi Watanabe; Kristy Wang; Ge Tao; Daniel P Judge; Michael R Zile; Takako Makita; Rupak Mukherjee; Henry M Sucov
TNNI3K expression worsens disease progression in several mouse heart pathology models. TNNI3K expression also reduces the number of diploid cardiomyocytes, which may be detrimental to adult heart regeneration. However, the gene is evolutionarily conserved, suggesting a beneficial function that has remained obscure. Here, we show that C57BL/6J-inbred Tnni3k mutant mice develop concentric remodeling
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Intragenic complementation of amino and carboxy terminal SMN missense mutations can rescue Smn null mice Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-21 Vicki L McGovern; Kaitlyn M Kray; W David Arnold; Sandra I Duque; Chitra C Iyer; Aurélie Massoni-Laporte; Eileen Workman; Aalapi Patel; Daniel J Battle; Arthur H M Burghes
Spinal muscular atrophy is caused by reduced levels of SMN resulting from the loss of SMN1 and reliance on SMN2 for the production of SMN. Loss of SMN entirely is embryonic lethal in mammals. There are several SMN missense mutations found in humans. These alleles do not show partial function in the absence of wild-type SMN and cannot rescue a null Smn allele in mice. However, these human SMN missense
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Genetic stratification of inherited and sporadic phaeochromocytoma and paraganglioma: implications for precision medicine Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-20 Ruth Casey; Hartmut P H Neumann; Eamonn R Maher
Over the past two decades advances in genomic technologies have transformed knowledge of the genetic basis of phaeochromocytoma and paraganglioma (PPGL). Though traditional teaching suggested that inherited cases accounted for only 10% of all phaeochromocytoma diagnosis, current estimates are at least three times this proportion. Inherited PPGL is a highly genetically heterogeneous disorder but the
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Genomics-based immuno-oncology: bridging the gap between immunology and tumor biology Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-20 Renzo G DiNatale; A Ari Hakimi; Timothy A Chan
The first hypotheses about how the immune system affects cancers were proposed in the early 20th century. These early concepts about cancer immunosurveillance were further developed in the decades that followed, but a detailed understanding of cancer immunity remained elusive. It was only recently, through the advent of high-throughput technologies, that scientists gained the ability to profile tumors
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Loss of epigenetic polarity is a hallmark of hematopoietic stem cell aging. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-08-21 Eva Mejia-Ramirez,Hartmut Geiger,M Carolina Florian
Changes of polarity in somatic stem cells upon aging or disease lead to a functional deterioration of stem cells and consequently loss of tissue homeostasis, likely due to changes in the mode (symmetry versus asymmetry) of stem cell divisions. Changes in polarity of epigenetic markers (or ‘epi-polarity’) in stem cells, which are linked to alterations in chromatin architecture, might explain how a decline
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Conditional deletion of SMN in cell culture identifies functional SMN alleles Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-19 Blatnik A, III, McGovern V, Le T, et al.
AbstractSpinal muscular atrophy (SMA) is caused by mutation or deletion of survival motor neuron 1 (SMN1) and retention of SMN2 leading to SMN protein deficiency. We developed an immortalized mouse embryonic fibroblast (iMEF) line in which full-length wild-type Smn (flwt-Smn) can be conditionally deleted using Cre recombinase. iMEFs lacking flwt-Smn are not viable. We tested the SMA patient SMN1 missense
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Germline variants are associated with increased primary melanoma tumor thickness at diagnosis Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-17 Mangantig E, MacGregor S, Iles M, et al.
AbstractGermline genetic variants have been identified, which predispose individuals and families to develop melanoma. Tumor thickness is the strongest predictor of outcome for clinically localized primary melanoma patients. We sought to determine whether there is a heritable genetic contribution to variation in tumor thickness. If confirmed, this will justify the search for specific genetic variants
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RNA-Seq profiling of leukocytes reveals a sex-dependent global circular RNA upregulation in multiple sclerosis and 6 candidate biomarkers Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-08 Leire Iparraguirre; Ainhoa Alberro; Lucía Sepúlveda; Iñaki Osorio-Querejeta; Laura Moles; Tamara Castillo-Triviño; Thomas B Hansen; Maider Muñoz-Culla; David Otaegui
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, with higher prevalence in women, that leads to neurological disability. The disease course and clinical phenotype are highly variable, and therefore, biomarkers for the diagnosis, classification, monitoring of the disease and treatment assessment are needed. Studies have shown a dysregulation in the coding and non-coding
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Ubiquitous expression of Akt1 p.(E17K) results in vascular defects and embryonic lethality in mice Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-08 Marjorie J Lindhurst; Wenling Li; Nathaniel Laughner; Jasmine J Shwetar; Hannah C Kondolf; Xuefei Ma; Yoh-suke Mukouyama; Leslie G Biesecker
Proteus syndrome is a progressive overgrowth disorder with vascular malformations caused by mosaic expression of the AKT1 c.49G > A, p.(E17K) activating variant which was predicted to cause lethality if expressed ubiquitously. To test that hypothesis, we used the ACTB-Cre gene to activate a conditional Akt1 p.(E17K) allele in the mouse. No offspring that was heterozygous for both Cre and the conditional
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Implicit Bias of Encoded Variables: Frameworks for addressing structured bias in EHR-GWAS Data. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-02 Hillary R Dueñas,Carina Seah,Jessica S Johnson,Laura M Huckins
The ‘discovery’ stage of genome-wide association studies required amassing large, homogeneous cohorts. In order to attain clinically useful insights, we must now consider the presentation of disease within our clinics and, by extension, within our medical records. Large-scale use of electronic health record (EHR) data can help to understand phenotypes in a scalable manner, incorporating lifelong and
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The phenomenal epigenome in neurodevelopmental disorders. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-08-07 Ummi Ciptasari,Hans van Bokhoven
Disruption of chromatin structure due to epimutations is a leading genetic etiology of neurodevelopmental disorders, collectively known as chromatinopathies. We show that there is an increasing level of convergence from the high diversity of genes that are affected by mutations to the molecular networks and pathways involving the respective proteins, the disrupted cellular and subcellular processes
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Genetic Risk Factors of ME/CFS: A Critical Review. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-08-03 Joshua J Dibble,Simon J McGrath,Chris P Ponting
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem illness that lacks effective therapy and a biomedical understanding of its causes. Despite a prevalence of ∼0.2–0.4% and its high public health burden, and evidence that it has a heritable component, ME/CFS has not yet benefited from the advances in technology and analytical tools that have improved our understanding
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Fine-mapping genetic associations. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-08-03 Anna Hutchinson,Jennifer Asimit,Chris Wallace
Whilst thousands of genetic variants have been associated with human traits, identifying the subset of those variants that are causal requires a further ‘fine-mapping’ step. We review the basic fine-mapping approach, which is computationally fast and requires only summary data, but depends on an assumption of a single causal variant per associated region which is recognized as biologically unrealistic
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Low-pass whole genome bisulfite sequencing of neonatal dried blood spots identifies a role for RUNX1 in Down syndrome DNA methylation profiles Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-10-01 Benjamin I Laufer; Hyeyeon Hwang; Julia M Jianu; Charles E Mordaunt; Ian F Korf; Irva Hertz-Picciotto; Janine M LaSalle
Neonatal dried blood spots (NDBS) are a widely banked sample source that enables retrospective investigation into early life molecular events. Here, we performed low-pass whole genome bisulfite sequencing (WGBS) of 86 NDBS DNA to examine early life Down syndrome (DS) DNA methylation profiles. DS represents an example of genetics shaping epigenetics, as multiple array-based studies have demonstrated
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Dystroglycan regulates proper expression, submembranous localisation and subsequent phosphorylation of Dp71 through physical interaction Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-30 Takahiro Fujimoto; Takeshi Yaoi; Hidekazu Tanaka; Kyoko Itoh
Dystrophin-dystroglycan complex (DGC) plays important roles for structural integrity and cell signaling, and its defects causes progressive muscular degeneration and intellectual disability. Dystrophin short product, Dp71 is abundantly expressed in multiple tissues other than muscle and is suspected of contributing to cognitive functions, however, its molecular characteristics and relation to dystroglycan
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Corrigendum to: The co-chaperone and reductase ERdj5 facilitates rod opsin biogenesis and quality control. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-28 Dimitra Athanasiou,Dalila Bevilacqua,Monica Aguila,Caroline McCulley,Naheed Kanuga,Takao Iwawaki,J Paul Chapple,Michael E Cheetham
AbstractAge-related macular degeneration (AMD) is a chronic, multifactorial disorder and a leading cause of blindness in the elderly. Characterized by progressive photoreceptor degeneration in the central retina, disease progression involves epigenetic changes in chromatin accessibility resulting from environmental exposures and chronic stress. Here, we report that a photosensitive mouse model of acute
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Specific ZNF274 binding interference at SNORD116 activates the maternal transcripts in Prader-Willi syndrome neurons. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-25 Maéva Langouët; Dea Gorka; Clarisse Orniacki; Clémence M Dupont-Thibert; Michael S Chung; Heather R Glatt-Deeley; Noelle Germain; Leann J Crandall; Justin L Cotney; Christopher E Stoddard; Marc Lalande; Stormy J Chamberlain
Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay, and hyperphagia/obesity. This disorder is caused by the absence of paternally-expressed gene products from chromosome 15q11-q13. We previously demonstrated that knocking out ZNF274, a KRAB-domain zinc finger protein capable of recruiting epigenetic machinery to deposit the H3K9me3 repressive histone modification
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Coenzyme Q10 modulates sulfide metabolism and links the mitochondrial respiratory chain to pathways associated to one carbon metabolism. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-25 Pilar González-García,Agustín Hidalgo-Gutiérrez,Cristina Mascaraque,Eliana Barriocanal-Casado,Mohammed Bakkali,Marcello Ziosi,Ussipbek Botagoz Abdihankyzy,Sabina Sánchez-Hernández,Germaine Escames,Holger Prokisch,Francisco Martín,Catarina M Quinzii,Luis C López
Abnormalities of one carbon, glutathione and sulfide metabolisms have recently emerged as novel pathomechanisms in diseases with mitochondrial dysfunction. However, the mechanisms underlying these abnormalities are not clear. Also, we recently showed that sulfide oxidation is impaired in Coenzyme Q10 (CoQ10) deficiency. This finding leads us to hypothesize that the therapeutic effects of CoQ10, frequently
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Genes influenced by MEF2C contribute to neurodevelopmental disease via gene expression changes that affect multiple types of cortical excitatory neurons. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-25 Donna Cosgrove,Laura Whitton,Laura Fahey,Pilib Ó Broin,Gary Donohoe,Derek W Morris
Myocyte enhancer factor 2 C (MEF2C) is an important transcription factor during neurodevelopment. Mutation or deletion of MEF2C causes intellectual disability (ID) and common variants within MEF2C are associated with cognitive function and schizophrenia risk. We investigated if genes influenced by MEF2C during neurodevelopment are enriched for genes associated with neurodevelopmental phenotypes, and
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A Novel Mouse Model for Pyridoxine-Dependent Epilepsy Due to Antiquitin Deficiency. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-24 Hilal H Al-Shekaili,Terri L Petkau,Izabella Pena,Tess C Lengyell,Nanda M Verhoeven-Duif,Jolita Ciapaite,Marjolein Bosma,Martijn van Faassen,Ido P Kema,Gabriella Horvath,Colin Ross,Elizabeth M Simpson,Jan M Friedman,Clara Karnebeek,Blair R Leavitt
Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disease caused by mutations in the ALDH7A1 gene leading to blockade of the lysine catabolism pathway. PDE is characterized by recurrent seizures that are resistant to conventional anticonvulsant treatment but are well-controlled by pyridoxine (PN). Most PDE patients also suffer from neurodevelopmental deficits despite adequate seizure
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FKBP8 variants are risk factors for spina bifida. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-24 Tian Tian,Xuanye Cao,Sung-Eun Kim,Ying Linda Lin,John W Steele,Robert M Cabrera,Menuka Karki,Wei Yang,Nicholas J Marini,Ethan N Hoffman,Xiao Han,Cindy Hu,Linlin Wang,Bogdan J Wlodarczyk,Gary M Shaw,Aiguo Ren,Richard H Finnell,Yunping Lei
Neural tube defects (NTDs) are a group of severe congenital malformations caused by a failure of neural tube closure during early embryonic development. Although extensively investigated, the genetic etiology of NTDs remains poorly understood. FKBP8 is critical for proper mammalian neural tube closure. Fkbp8−/− mouse embryos showed posterior NTDs consistent with a diagnosis of spina bifida (SB). To
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Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in spinocerebellar ataxia type 1. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-23 Ravi Chopra,David D Bushart,John P Cooper,Dhananjay Yellajoshyula,Logan M Morrison,Haoran Huang,Hillary P Handler,Luke J Man,Warunee Dansithong,Daniel R Scoles,Stefan M Pulst,Harry T Orr,Vikram G Shakkottai
Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from
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Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-22 Wenfei Liu,Orjona Taso,Rui Wang,Sevinc Bayram,Andrew C Graham,Pablo Garcia-Reitboeck,Anna Mallach,William D Andrews,Thomas M Piers,Juan A Botia,Jennifer M Pocock,Damian M Cummings,John Hardy,Frances A Edwards,Dervis A Salih
Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer’s disease (ad). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-in mice heterozygous or homozygous for the Trem2 R47H ad risk
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Novel TONSL variants cause SPONASTRIME dysplasia and associate with spontaneous chromosome breaks, defective cell proliferation and apoptosis. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-21 Lucia Micale,Samantha Cialfi,Carmela Fusco,Luigia Cinque,Stefano Castellana,Tommaso Biagini,Claudio Talora,Angelantonio Notarangelo,Luigi Bisceglia,Domenica Taruscio,Marco Salvatore,Marco Castori
SPONASTRIME dysplasia is an ultrarare spondyloepimetaphyseal dysplasia featuring short stature and short limbs, platyspondyly, depressed nasal bridge with midface hypoplasia, and striated metaphyses. In 2019, an autosomal recessive inheritance was demonstrated by the identification of bi-allelic hypomorphic alleles in TONSL. The encoded protein has a critical role in maintaining genome integrity by
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The Duffy-null genotype and risk of infection. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-22 Sophie E Legge,Rune H Christensen,Liselotte Petersen,Antonio F Pardiñas,Matthew Bracher-Smith,Steven Knapper,Jonas Bybjerg-Grauholm,Marie Baekvad-Hansen,David M Hougaard,Thomas Werge,Merete Nordentoft,Preben Bo Mortensen,Michael J Owen,Michael C O'Donovan,Michael E Benros,James T R Walters
Many medical treatments, from oncology to psychiatry, can lower white blood cell counts and thus access to these treatments can be restricted to individuals with normal levels of white blood cells, principally in order to minimize risk of serious infection. This adversely affects individuals of African or Middle Eastern ancestries who have on average a reduced number of circulating white blood cells
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The mechanistic role of alpha-synuclein in the nucleus: impaired nuclear function caused by familial Parkinson's disease SNCA mutations. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-19 Vivian Chen,Malik Moncalvo,Dominic Tringali,Lidia Tagliafierro,Ahila Shriskanda,Ekaterina Ilich,Wendy Dong,Boris Kantor,Ornit Chiba-Falek
Alpha-synuclein SNCA has been implicated in the etiology of Parkinson’s disease (PD); however, the normal function of alpha-synuclein protein and the pathway that mediates its pathogenic effect is yet to be discovered. We investigated the mechanistic role of SNCA in the nucleus utilizing isogenic human-induced pluripotent stem cells-derived neurons from PD patients with autosomal dominant mutations
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Shorter telomere length, higher telomerase activity in association with Tankyrase gene Polymorphism contribute to High-altitude pulmonary edema. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-11 Manjula Miglani,Manjari Rain,Qadar Pasha,V Samuel Raj,Tashi Thinlas,Ghulam Mohammad,Archana Gupta,Ramendra Pati Pandey,Arpana Vibhuti
High-altitude pulmonary edema (HAPE) is a non-cardiogenic form of pulmonary edema, which is induced upon exposure to hypobaric hypoxia at high-altitude (HA). Hypobaric hypoxia generates reactive oxygen species that may damage telomeres and disturb normal physiological processes. Telomere complex comprises of multiple proteins, of which, tankyrase (TNKS) is actively involved in DNA damage repairs. We
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Regulation of telomeric function by DNA methylation differs between humans and mice. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-11 Shir Toubiana,Gal Larom,Riham Smoom,Robert J Duszynski,Lucy A Godley,Claire Francastel,Guillaume Velasco,Sara Selig
The most distal 2 kb region in the majority of human subtelomeres contains CpG-rich promoters for TERRA, a long non-coding RNA. When the function of the de novo DNA methyltransferase DNMT3B is disrupted, as in ICF1 syndrome, subtelomeres are abnormally hypomethylated, subtelomeric heterochromatin acquires open chromatin characteristics, TERRA is highly expressed, and telomeres shorten rapidly. In this
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Brain ventricular enlargement in human and murine acute intermittent porphyria. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-11 Daniel Jericó,Elkin O Luis,Lorena Cussó,María A Fernández-Seara,Xabier Morales,Karol M Córdoba,Marina Benito,Ana Sampedro,María Larriva,María J Ramírez,Rafael Enríquez de Salamanca,Carlos Ortiz-de-Solorzano,Manuel Alegre,Jesús Prieto,José Luis Lanciego,Delia D'Avola,Gloria Gonzalez-Aseguinolaza,María A Pastor,Manuel Desco,Antonio Fontanellas
The morphological changes that occur in the central nervous system of patients with severe acute intermittent porphyria (AIP) have not yet been clearly established. The aim of this work was to analyse brain involvement in patients with severe AIP without epileptic seizures or clinical posterior reversible encephalopathy syndrome, as well as in a mouse model receiving or not liver-directed gene therapy
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LRP2 controls sonic hedgehog-dependent differentiation of cardiac progenitor cells during outflow tract formation. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-08 Annabel Christ,Maike Marczenke,Thomas E Willnow
Conotruncal malformations are a major cause of congenital heart defects in newborn infants. Recently, genetic screens in humans and in mouse models have identified mutations in LRP2, a multi-ligand receptor, as a novel cause of a common arterial trunk, a severe form of outflow tract (OFT) defect. Yet, the underlying mechanism why the morphogen receptor LRP2 is essential for OFT development remained
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Aberrant Early Growth of Individual Trigeminal Sensory and Motor Axons in a Series of Mouse Genetic Models of 22q11.2 Deletion Syndrome. Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-09-08 Zahra Motahari,Thomas M Maynard,Anastas Popratiloff,Sally A Moody,Anthony-S LaMantia
We identified divergent modes of initial axon growth that prefigure disrupted differentiation of the trigeminal nerve (CN V), a cranial nerve essential for suckling, feeding and swallowing (S/F/S), a key innate behavior compromised in multiple genetic developmental disorders including DiGeorge/22q11.2 Deletion Syndrome (22q11.2 DS). We combined rapid in vivo labeling of single CN V axons in LgDel+/−