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  • An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-06-12
    Nicola Bedoni,Mathieu Quinodoz,Michele Pinelli,Gerarda Cappuccio,Annalaura Torella,Vincenzo Nigro,Francesco Testa,Francesca Simonelli,,Marta Corton,Susanna Lualdi,Federica Lanza,Giovanni Morana,Carmen Ayuso,Maja Di Rocco,Mirella Filocamo,Sandro Banfi,Nicola Brunetti-Pierri,Andrea Superti-Furga,Carlo Rivolta

    We investigated the genetic origin of the phenotype displayed by three children from two unrelated Italian families, presenting with a previously unrecognized autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA), as well as some brain anomalies that were visible at the MRI

    更新日期:2020-08-04
  • Male Sterility and Reduced Female Fertility in SCAPER-Deficient Mice.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-06-08
    Yasmin Tatour,Hadas Bar-Joseph,Ruth Shalgi,Tamar Ben-Yosef

    Mutations in S-phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER) cause a recessively inherited multisystemic disorder whose main features are retinal degeneration and intellectual disability. SCAPER, originally identified as a cell cycle regulator, was also suggested to be a ciliary protein. Because Scaper mutant males are sterile, we set up to characterize their phenotype. The

    更新日期:2020-08-04
  • Correction of amyotrophic lateral sclerosis related phenotypes in induced pluripotent stem cell-derived motor neurons carrying a hexanucleotide expansion mutation in C9orf72 by CRISPR/Cas9 genome editing using homology-directed repair.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-06-05
    Nidaa A Ababneh,Jakub Scaber,Rowan Flynn,Andrew Douglas,Paola Barbagallo,Ana Candalija,Martin R Turner,David Sims,Ruxandra Dafinca,Sally A Cowley,Kevin Talbot

    The G4C2 hexanucleotide repeat expansion (HRE) in C9orf72 is the commonest cause of familial amyotrophic lateral sclerosis (ALS). A number of different methods have been used to generate isogenic control lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and non-homologous end-joining by deleting the repeat region, with the risk of creating indels and genomic instability

    更新日期:2020-08-04
  • A Global Slc7a7 Knockout Mouse Model Demonstrates Characteristic Phenotypes of Human Lysinuric Protein Intolerance.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-06-05
    Bridget M Stroup,Ronit Marom,Xiaohui Li,Chih-Wei Hsu,Cheng-Yen Chang,Luan D Truong,Brian Dawson,Ingo Grafe,Yuqing Chen,Ming-Ming Jiang,Denise Lanza,Jennie Rose Green,Qin Sun,J P Barrish,Safa Ani,Audrey E Christiansen,John R Seavitt,Mary E Dickinson,Farrah Kheradmand,Jason D Heaney,Brendan Lee,Lindsay C Burrage

    Lysinuric protein intolerance (LPI) is an inborn error of cationic amino acid (arginine, lysine, ornithine) transport caused by biallelic pathogenic variants in SLC7A7, which encodes the light subunit of the y+LAT1 transporter. Treatments for the complications of LPI, including growth failure, renal disease, pulmonary alveolar proteinosis, autoimmune disorders and osteoporosis, are limited. Given the

    更新日期:2020-08-04
  • Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-06-05
    Anne Slavotinek,Doriana Misceo,Stephanie Htun,Linda Mathisen,Eirik Frengen,Michelle Foreman,Jennifer E Hurtig,Liz Enyenihi,Maria C Sterrett,Sara W Leung,Dina Schneidman-Duhovny,Juvianee Estrada-Veras,Jacque L Duncan,Charlotte A Haaxma,Erik-Jan Kamsteeg,Vivian Xia,Daniah Beleford,Yue Si,Ganka Douglas,Hans Einar Treidene,Ambro van Hoof,Milo B Fasken,Anita H Corbett

    The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills,

    更新日期:2020-08-04
  • Overexpression of Staufen1 in DM1 mouse skeletal muscle exacerbates dystrophic and atrophic features.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-06-05
    Tara E Crawford Parks,Kristen A Marcellus,Christine Péladeau,Bernard J Jasmin,Aymeric Ravel-Chapuis

    In myotonic dystrophy type 1 (DM1), the CUG expansion (CUGexp) in the 3′ untranslated region of the dystrophia myotonica protein kinase messenger ribonucleic acid affects the homeostasis of ribonucleic acid-binding proteins, causing the multiple symptoms of DM1. We have previously reported that Staufen1 is increased in skeletal muscles from DM1 mice and patients and that sustained Staufen1 expression

    更新日期:2020-08-04
  • Population specific reference panels are crucial for genetic analyses: an example of the CREBRF locus in Native Hawaiians.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-06-03
    Meng Lin,Christian Caberto,Peggy Wan,Yuqing Li,Annette Lum-Jones,Maarit Tiirikainen,Loreall Pooler,Brooke Nakamura,Xin Sheng,Jacqueline Porcel,Unhee Lim,Veronica Wendy Setiawan,Loïc Le Marchand,Lynne R Wilkens,Christopher A Haiman,Iona Cheng,Charleston W K Chiang

    Statistical imputation applied to genome-wide array data is the most cost-effective approach to complete the catalog of genetic variation in a study population. However, imputed genotypes in underrepresented populations incur greater inaccuracies due to ascertainment bias and a lack of representation among reference individuals, further contributing to the obstacles to study these populations. Here

    更新日期:2020-08-04
  • Laminin-111 protein therapy after disease onset slows muscle disease in a mouse model of Laminin-α2 related congenital muscular dystrophy.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-05-29
    Pamela Barraza-Flores,Katherine E Bukovec,Marisela Dagda,Brandon W Conner,Ariany Oliveira-Santos,Robert W Grange,Dean J Burkin

    Laminin-α2 related congenital muscular dystrophy (LAMA2-CMD) is a fatal muscle disease caused by mutations in the LAMA2 gene. Laminin-α2 is critical for the formation of laminin-211 and -221 heterotrimers in the muscle basal lamina. LAMA2-CMD patients exhibit hypotonia from birth and progressive muscle loss that results in developmental delay, confinement to a wheelchair, respiratory insufficiency

    更新日期:2020-08-04
  • Ovotesticular disorders of sex development (DSD) in FGF9 mouse models of human synostosis syndromes.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-05-26
    Anthony D Bird,Brittany M Croft,Masayo Harada,Lingyun Tang,Liang Zhao,Zhenhua Ming,Stefan Bagheri-Fam,Peter Koopman,Zhugang Wang,Keiichi Akita,Vincent R Harley

    In mice, male sex determination depends on FGF9 signalling via FGFR2c in the bipotential gonads to maintain the expression of the key testis gene SOX9. In humans, however, while FGFR2 mutations have been linked to 46,XY disorders of sex development (DSD), the role of FGF9 is unresolved. The only reported pathogenic mutations in human FGF9, FGF9S99N and FGF9R62G, are dominant and result in craniosynostosis

    更新日期:2020-08-04
  • A Drosophila model of Friedreich Ataxia with CRISPR/Cas9 insertion of GAA repeats in the frataxin gene reveals in vivo protection by N-acetyl cysteine
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-08-03
    Maria Russi; Elodie Martin; Benoit D’Autréaux; Laura Tixier; Hervé Tricoire; Véronique Monnier

    Friedreich Ataxia (FA) is caused by GAA repeat expansions in the first intron of FXN, the gene encoding frataxin, which results in decreased gene expression. Thanks to the high degree of frataxin conservation, the Drosophila melanogaster fruitfly appears as an adequate animal model to study this disease and to evaluate therapeutic interventions. Here, we generated a Drosophila model of FA with CRISPR/Cas9

    更新日期:2020-08-03
  • 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 approximately 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

    更新日期:2020-08-03
  • SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialisation
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-08-03
    Helen J Kuht; Jinu Han; Gail D E Maconachie; Sung Eun Park; Seung-Tae Lee; Rebecca McLean; Viral Sheth; Michael Hisaund; Basu Dawar; Nicolas Sylvius; Usman Mahmood; Frank A Proudlock; Irene Gottlob; Hyun Taek Lim; Mervyn G Thomas

    FHONDA (foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis) is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this

    更新日期:2020-08-03
  • Skeletal muscle regeneration in Facioscapulohumeral muscular dystrophy is correlated with pathological severity
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-08-03
    Christopher R S Banerji; Don Henderson; Rabi N Tawil; Peter S Zammit

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant myopathy, characterised by slowly progressive skeletal muscle weakness and wasting. While a regenerative response is often provoked in many muscular dystrophies, little is known about whether a regenerative response is regularly elicited in FSHD muscle. For comparison, we also examined the similarly slowly progressing Myotonic Dystrophy

    更新日期:2020-08-03
  • The role of the stem cell epigenome in normal aging and rejuvenative therapy
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-08-03
    Jeyan Jayarajan; Michael D Milsom

    Adult stem cells are ultimately responsible for the lifelong maintenance of regenerating of tissues during both homeostasis and following injury. Hence, the functional attrition of adult stem cells is thought to be an important driving factor behind the progressive functional decline of tissues and organs that is observed during aging. The mechanistic cause underlying this age-associated exhaustion

    更新日期:2020-08-03
  • Metabolic stress regulates genome-wide transcription in a PTEN-dependent manner
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-08-03
    Ata Abbas; Roshan Padmanabhan; Charis Eng

    PTEN is implicated in a wide variety of pathophysiological conditions and traditionally studied in the context of the PIK3-AKT–mTOR axis. Recent studies from our group and others have reported a novel role of PTEN in the regulation of transcription at the genome-wide scale. This emerging role of PTEN on global transcriptional regulation is providing a better understanding of various diseases, including

    更新日期:2020-08-03
  • Chronic lymphocytic leukemia (CLL) risk is mediated by multiple enhancer variants within CLL risk loci
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-08-03
    Huihuang Yan; Shulan Tian; Geffen Kleinstern; Zhiquan Wang; Jeong-Heon Lee; Nicholas J Boddicker; James R Cerhan; Neil E Kay; Esteban Braggio; Susan L Slager

    Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. It has a strong genetic basis, showing a ~ 8-fold increased risk of CLL in first-degree relatives. Genome-wide association studies (GWAS) have identified 41 risk variants across 41 loci. However, for a majority of the loci, the functional variants and the mechanisms underlying their causal roles remain undefined

    更新日期:2020-08-03
  • Fine-mapping genetic associations
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-08-03
    Anna Hutchinson; Jennifer Asimit; Chris Wallace

    While 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 standard 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 recognised as biologically unrealistic

    更新日期:2020-08-03
  • Corrigendum to: Drosophila clueless is involved in Parkin-dependent mitophagy by promoting VCP-mediated Marf degradation.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-06-08
    Zong-Heng Wang,Cheryl Clark,Erika R Geisbrecht

    The authors apologize for the errors in Figure 6E. An unfinished version of the figure that contained duplicated images of the changes in mitochondrial morphology, mCherry-Atg8a and p62 localization was mistakenly uploaded in the final submission. The main conclusions in Figs. 6F and 6G remain the same as the quantifications were calculated from original images of the indicated genotypes. Corrected

    更新日期:2020-07-30
  • Disruption of foxc1 genes in zebrafish results in dosage-dependent phenotypes overlapping Axenfeld-Rieger syndrome
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-28
    Jesús-José Ferre-Fernández; Elena A Sorokina; Samuel Thompson; Ross F Collery; Emily Nordquist; Joy Lincoln; Elena V Semina

    The Forkhead Box C1 (FOXC1) gene encodes a forkhead/winged helix transcription factor involved in embryonic development. Mutations in this gene cause dysgenesis of the anterior segment of the eye, most commonly Axenfeld-Rieger syndrome (ARS), often with other systemic features. The developmental mechanisms and pathways regulated by FOXC1 remain largely unknown. There are two conserved orthologs of

    更新日期:2020-07-28
  • Insights into genetic variants associated with NASH-fibrosis from metabolite profiling
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-28
    Jake P Mann; Maik Pietzner; Laura B Wittemans; Emmanuela De Lucia Rolfe; Nicola D Kerrison; Fumiaki Imamura; Nita G Forouhi; Eric Fauman; Michael E Allison; Jules L Griffin; Albert Koulman; Nicholas J Wareham; Claudia Langenberg

    Several genetic discoveries robustly implicate five single nucleotide variants in the progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and fibrosis (NASH-fibrosis), including a recently identified variant in MTARC1. To better understand these variants as potential therapeutic targets, we aimed to characterize their impact on metabolism using comprehensive metabolomics

    更新日期:2020-07-28
  • Genome-wide association study of corneal biomechanical properties identifies over 200 loci providing insight into the genetic aetiology of ocular diseases
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-27
    Mark J Simcoe; Anthony P Khwaja; U K Biobank Eye; Vision Consortium; Pirro G Hysi; Christopher J Hammond

    Corneal hysteresis and corneal resistance factor are parameters which reflect the dynamic biomechanical properties of the cornea and have been shown to be biomarkers of corneal disease. In this genome-wide association study of over 100 000 participants we identified over 200 genetic loci, all but eight novel, significantly associated with either one or both of these traits. In addition to providing

    更新日期:2020-07-28
  • Multiplex melanoma families are enriched for polygenic risk
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-27
    Matthew H Law; Lauren G Aoude; David L Duffy; Georgina V Long; Peter A Johansson; Antonia L Pritchard; Kiarash Khosrotehrani; Graham J Mann; Grant W Montgomery; Mark M Iles; Anne E Cust; Jane M Palmer; Kerwin F Shannon; Andrew J Spillane; Jonathan R Stretch; John F Thompson; Robyn P M Saw; Richard A Scolyer; Nicholas G Martin; Nicholas K Hayward; Stuart MacGregor

    Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental aetiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous

    更新日期:2020-07-28
  • Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-27
    Qing Chen; Hanni Ke; Xuezhen Luo; Lingbo Wang; Yanhua Wu; Shuyan Tang; Jinsong Li; Li Jin; Feng Zhang; Yingying Qin; Xiaojun Chen

    Losing of ovarian functions prior to natural menopause age causes female infertility and early menopause. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before 40 years of age. Known genetic causes account for 25%—30% of POI cases, demonstrating the high genetic heterogeneity of POI and the necessity for further genetic explorations. Here we conducted genetic analyses

    更新日期:2020-07-28
  • Erbb4 regulates the oocyte microenvironment during folliculogenesis
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-27
    Ville Veikkolainen; Nsrein Ali; Milena Doroszko; Antti Kiviniemi; Ilkka Miinalainen; Claes Ohlsson; Matti Poutanen; Nafis Rahman; Klaus Elenius; Seppo J Vainio; Florence Naillat

    Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders leading to infertility in women affecting reproductive, endocrine and metabolic systems. Recent genome-wide association studies on PCOS cohorts revealed a single nucleotide polymorphism (SNP) in the ERBB4 receptor tyrosine kinase 4 gene, but its role in ovary development or during folliculogenesis remains poorly understood

    更新日期:2020-07-27
  • ROM1 contributes to phenotypic heterogeneity in PRPH2-associated retinal disease
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-27
    Daniel Strayve; Mustafa M Makia; Mashal Kakakhel; Haarthi Sakthivel; Shannon M Conley; Muayyad R Al-Ubaidi; Muna I Naash

    Peripherin 2 (PRPH2) is a retina-specific tetraspanin protein essential for the formation of rod and cone photoreceptor outer segments (OS). Patients with mutations in PRPH2 exhibit severe retinal degeneration characterized by vast inter- and intra-familial phenotypic heterogeneity. To help understand contributors to this within-mutation disease variability, we asked whether the PRPH2 binding partner

    更新日期:2020-07-27
  • Lysine acetylation regulates the RNA binding, subcellular localization and inclusion formation of FUS
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-21
    Alexandra Arenas; Jing Chen; Lisha Kuang; Kelly R Barnett; Edward J Kasarskis; Jozsef Gal; Haining Zhu

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the preferential death of motor neurons. Approximately 10% of ALS cases are familial and 90% are sporadic. Fused in Sarcoma (FUS) is a ubiquitously expressed RNA binding protein implicated in familial ALS and frontotemporal dementia (FTD). The physiological function and pathological mechanism of FUS are not well understood

    更新日期:2020-07-27
  • Epigenetic hallmarks of age-related macular degeneration are recapitulated in a photosensitive mouse model
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-21
    Jennings Luu; Les Kallestad; Thanh Hoang; Dominik Lewandowski; Zhiqian Dong; Seth Blackshaw; Krzysztof Palczewski

    Age-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 stress-induced

    更新日期:2020-07-21
  • Fine-scale population structure in the UK Biobank: implications for genome-wide association studies
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-21
    James P Cook; Anubha Mahajan; Andrew P Morris

    The UK Biobank is a prospective study of more than 500 000 participants that has aggregated data from questionnaires, physical measures, biomarkers, imaging and follow-up for a wide range of health-related outcomes, together with genome-wide genotyping supplemented with high-density imputation. Previous studies have highlighted fine-scale population structure in the UK on a North-West to South-East

    更新日期:2020-07-21
  • Analysis of putative cis-regulatory elements regulating blood pressure variation.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-05-21
    Priyanka Nandakumar,Dongwon Lee,Thomas J Hoffmann,Georg B Ehret,Dan Arking,Dilrini Ranatunga,Man Li,Megan L Grove,Eric Boerwinkle,Catherine Schaefer,Pui-Yan Kwok,Carlos Iribarren,Neil Risch,Aravinda Chakravarti

    Hundreds of loci have been associated with blood pressure (BP) traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~100 000 Genetic Epidemiology Research on Aging study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining

    更新日期:2020-07-21
  • Ubiquilin-2 differentially regulates polyglutamine disease proteins
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-18
    Julia E Gerson; Nathaniel Safren; Svetlana Fischer; Ronak Patel; Emily V Crowley; Jacqueline P Welday; Alexandra K Windle; Sami Barmada; Henry L Paulson; Lisa M Sharkey

    Divergent protein context helps explain why polyglutamine expansion diseases differ clinically and pathologically. This heterogeneity may also extend to how polyglutamine disease proteins are handled by cellular pathways of proteostasis. Studies suggest, for example, that the ubiquitin-proteasome shuttle protein Ubiquilin-2 (UBQLN2) selectively interacts with specific polyglutamine disease proteins

    更新日期:2020-07-18
  • Regulation, Diversity and Function of MECP2 Exon and 3’UTR Isoforms
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-18
    Deivid Carvalho Rodrigues; Marat Mufteev; James Ellis

    The methyl-CpG binding protein 2 (MECP2) is a critical global regulator of gene expression. Mutations in MECP2 cause neurodevelopmental disorders including Rett syndrome (RTT). MECP2 exon 2 is spliced into two alternative mRNA isoforms encoding MECP2-E1 or MECP2-E2 protein isoforms that differ in their N-termini. MECP2-E2, isolated first was used to define the general roles of MECP2 in methyl-DNA binding

    更新日期:2020-07-18
  • Genetics of Early Growth Traits
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-16
    Diana L Cousminer; Rachel M Freathy

    AbstractmRNA processing is highly regulated during development through changes in RNA-binding protein (RBP) activities. CUG-BP, Elav-like family member 1 (CELF1, also called CUGBP1) is an RBP, the expression of which decreases in skeletal muscle soon after birth. CELF1 regulates multiple nuclear and cytoplasmic RNA processing events. In the nucleus, CELF1 regulates networks of postnatal alternative

    更新日期:2020-07-16
  • Transcriptomic and epigenomic dynamics associated with development of human iPSC-derived GABAergic interneurons†
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-16
    George Andrew S Inglis; Ying Zhou; Dillon G Patterson; Christopher D Scharer; Yanfei Han; Jeremy M Boss; Zhexing Wen; Andrew Escayg

    GABAergic interneurons (GINs) are a heterogeneous population of inhibitory neurons that collectively contribute to the maintenance of normal neuronal excitability and network activity. Identification of the genetic regulatory elements and transcription factors that contribute toward GIN function may provide new insight into the pathways underlying proper GIN activity, while also indicating potential

    更新日期:2020-07-16
  • UPF3B mutations including a novel synonymous variant associated with absent speech implicate nonsense mediated mRNA decay as a regulator of neurodevelopmental disorder gene networks.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-15
    Deepti Domingo; Urwah Nawaz; Mark Corbett; Josh L Espinoza; Katrina Tatton-Brown; David Coman; Miles F Wilkinson; Jozef Gecz; Lachlan A Jolly

    Loss-of-function mutations of the X-chromosome gene UPF3B cause male neurodevelopmental disorders (NDDs) via largely unknown mechanisms. We investigated initially by interrogating a novel synonymous UPF3B variant in a male with absent speech. In-silico and functional studies using cell lines derived from this individual show altered UPF3B RNA splicing. The resulting mRNA species encodes a frame-shifted

    更新日期:2020-07-15
  • Molecular tumor classification using DNA methylome analysis
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-13
    Martin Sill; Christoph Plass; Stefan M Pfister; Daniel B Lipka

    Tumor classifiers based on molecular patterns promise to define and reliably classify tumor entities. The high tissue- and cell type-specificity of DNA methylation, as well as its high stability, makes DNA methylation an ideal choice for the development of tumor classifiers. Herein, we review existing tumor classifiers using DNA methylome analysis and will provide an overview on their emerging impact

    更新日期:2020-07-13
  • Altered bone development with impaired cartilage formation precedes neuromuscular symptoms in Spinal Muscular Atrophy (SMA)
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-09
    Niko Hensel; Hermann Brickwedde; Konstantinos Tsaknakis; Antonia Grages; Lena Braunschweig; Katja A Lüders; Heiko M Lorenz; Sebastian Lippross; Lisa M Walter; Frank Tavassol; Stefan Lienenklaus; Claudia Neunaber; Peter Claus; Anna K Hell

    Spinal Muscular Atrophy (SMA) is a fatal neurodegenerative disease of newborns and children caused by mutations or deletions of the Survival of motoneuron gene 1 (SMN1) resulting in low levels of the SMN protein. While neuromuscular degeneration is the cardinal symptom of the disease, the reduction of the ubiquitously expressed SMN additionally elicits non-motoneuron symptoms. Impaired bone development

    更新日期:2020-07-09
  • Functional annotation of genomic variation: DNA methylation episignatures in neurodevelopmental Mendelian disorders
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-09
    Bekim Sadikovic; Michael A Levy; Erfan Aref-Eshghi

    The breadth and complexity of genetic testing in patients with suspected Mendelian neurodevelopmental disorders has rapidly expanded in the past two decades. However, in spite of advances in genomic technologies, genetic diagnosis remains elusive in more than half of these patients. Epigenomics, and in particular genomic DNA methylation profiles, are now known to be associated with the underpinning

    更新日期:2020-07-09
  • Pre-natal manifestation of systemic developmental abnormalities in spinal muscular atrophy
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-09
    Anna A L Motyl; Kiterie M E Faller; Ewout J N Groen; Rachel A Kline; Samantha L Eaton; Leire M Ledahawsky; Helena Chaytow; Douglas J Lamont; Thomas M Wishart; Yu-Ting Huang; Thomas H Gillingwater

    Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in survival motor neuron 1 (SMN1). SMN-restoring therapies have recently emerged; however, pre-clinical and clinical studies revealed a limited therapeutic time-window and systemic aspects of the disease. This raises a fundamental question of whether SMA has pre-symptomatic, developmental components to disease pathogenesis

    更新日期:2020-07-09
  • The mechanistic GEMMs of oncogenic histones
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-08
    Anders M Lindroth; Yoon Jung Park; Verónica Matía; Massimo Squatrito

    The last decade’s progress unraveling the mutational landscape of all age groups of cancer has uncovered mutations in histones as vital contributors of tumorigenesis. Here we review three new aspects of oncogenic histones: first, the identification of additional histone mutations potentially contributing to cancer formation; second, tumors expressing histone mutations to study the crosstalk of post-translational

    更新日期:2020-07-08
  • Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-07
    Ricardo Mouro; Larissa Arning; James V Giordano; Pedram Razghandi; Marissa A Andrew; Tammy Gillis; Kevin Correia; Jayalakshmi S Mysore; Debora-M Grote Urtubey; Constanze R Parwez; Sarah M von Hein; H Brent Clark; Huu Phuc Nguyen; Eckart Förster; Allison Beller; Suman Jayadaev; C Dirk Keene; Thomas D Bird; Diane Lucente; Jean-Paul Vonsattel; Harry Orr; Carsten Saft; Elisabeth Petrasch-Parwez; Vanessa

    The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans we performed comprehensive quantitative analyses of CAG expansion in ~ 50 central nervous system (CNS) and peripheral postmortem tissues from

    更新日期:2020-07-07
  • Motor neuron translatome reveals deregulation of SYNGR4 and PLEKHB1 in mutant TDP-43 amyotrophic lateral sclerosis models
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-07
    Rita F Marques; Jan B Engler; Katrin Küchler; Ross A Jones; Thomas Lingner; Gabriela Salinas; Thomas H Gillingwater; Manuel A Friese; Kent E Duncan

    Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease with progressive loss of motor neuron (MN) function in the brain and spinal cord. Mutations in TARDBP, encoding the RNA-binding protein TDP-43, are one cause of ALS and TDP-43 mislocalization in MNs is a key pathological feature of > 95% of ALS cases. While numerous studies support altered RNA regulation by TDP-43 as a major cause

    更新日期:2020-07-07
  • Targeted Chromatin Conformation (T2C) analysis identifies novel distal neural enhancers of ZEB2 in pluripotent stem cell differentiation
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-06
    Judith C Birkhoff; Rutger W W Brouwer; Petros Kolovos; Anne L Korporaal; Ana Bermejo-Santos; Ilias Boltsis; Karol Nowosad; Mirjam C G N Hout; Frank G Grosveld; Wilfred F J van IJcken; Danny Huylebroeck; Andrea Conidi

    The transcription factor ZEB2 controls embryonic and adult cell fate decisions and cellular maturation in many stem/progenitor cell types. Defects in these processes in specific cell types underlie several aspects of Mowat-Wilson syndrome (MOWS), which is caused by ZEB2 haplo-insufficiency. Human ZEB2, like mouse Zeb2, is located on chromosome 2 downstream of a ± 3.5 Mb-long gene-desert, lacking any

    更新日期:2020-07-06
  • Retrovirus reactivation in CHMP2BIntron5 models of Frontotemporal Dementia
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-06
    Laura Fort-Aznar; Chris Ugbode; Sean T Sweeney

    Frontotemporal dementia (FTD) is the second most prevalent form of pre-senile dementia after Alzheimer’s disease. Amyotrophic lateral sclerosis (ALS) can overlap genetically, pathologically and clinically with FTD indicating the two conditions are ends of a spectrum and may share common pathological mechanisms. FTD-ALS causing mutations are known to be involved in endosomal trafficking and RNA regulation

    更新日期:2020-07-06
  • Skewed allelic expression on X-chromosome associated with aberrant expression of XIST on systemic lupus erythematosus lymphocytes
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-06
    Yanfeng Zhang; Xinrui Li; Andrew Gibson; Jeffrey Edberg; Robert P Kimberly; Devin M Absher

    A common feature of autoimmune diseases, including systemic lupus erythematosus (SLE), is an increased prevalence in women. However, the molecular basis for sex disparity in SLE remains poorly understood. To examine the role of X-linked transcription in SLE adaptive immune cells, we performed RNA-seq in T-cell and B-cell subsets from either healthy donors or patients with SLE. Analyses of allelic expression

    更新日期:2020-07-06
  • Correction of cilia structure and function alleviates multi-organ pathology in Bardet-Biedl Syndrome mice
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-03
    Hervé Husson; Nikolay O Bukanov; Sarah Moreno; Mandy M Smith; Brenda Richards; Cheng Zhu; Tyler Picariello; Hyejung Park; Bing Wang; Thomas A Natoli; Laurie A Smith; Stefano Zanotti; Ryan J Russo; Stephen L Madden; Katherine W Klinger; Vijay Modur; Oxana Ibraghimov-Beskrovnaya

    Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive ciliopathy affecting multiple organs. The development of potential disease-modifying therapy for BBS will require concurrent targeting of multi-systemic manifestations. Here, we show for the first time that monosialodihexosylganglioside accumulates in Bbs2−/− cilia, indicating impairment of glycosphingolipid (GSL) metabolism in BBS. Consequently

    更新日期:2020-07-06
  • Pharmacogenomics for Immunotherapy and Immune-related Cardiotoxicity
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-03
    Jessica A Castrillon; Charis Eng; Feixiong Cheng

    Immune checkpoint blockade (ICB) has become a standard of care in a subset of solid tumors. Although cancer survivorship has extended, rates of durable response of ICB remain poor; furthermore, cardiac adverse effects are emerging which impacts several mechanical aspects of the heart. Cardio-oncology programs implement a clinical assessment to curtail cardiovascular disease progression but are limited

    更新日期:2020-07-06
  • TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-03
    Erica E Davis; Ravikumar Balasubramanian; Zachary A Kupchinsky; David L Keefe; Lacey Plummer; Kamal Khan; Blazej Meczekalski; Karen E Heath; Vanesa Lopez-Gonzalez; Mary J Ballesta-Martinez; Gomathi Margabanthu; Susan Price; James Greening; Raja Brauner; Irene Valenzuela; Ivon Cusco; Paula Fernandez-Alvarez; Margaret E Wierman; Taibo Li; Kasper Lage; Priscila Sales Barroso; Yee-Ming Chan; William F

    Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD). Here we report thirteen

    更新日期:2020-07-06
  • The Emerging Field of Polygenic Risk Scores and Perspective for Use in Clinical Care
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-03
    Tatiane Yanes; Aideen M McInerney-Leo; Matthew Law; Shelly Cummings

    Genetic testing is used widely for diagnostic, carrier and predictive testing in monogenic diseases. Until recently, there were no genetic testing options available for multifactorial complex diseases like heart disease, diabetes, and cancer. Genome wide association studies (GWAS) have been invaluable in identifying single nucleotide polymorphisms (SNPs), associated with increased or decreased risk

    更新日期:2020-07-06
  • Spatial genome architecture and the emergence of malignancy
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-07-03
    Adi Danieli; Argyris Papantonis

    Human chromosomes are large spatially- and hierarchically-structured entities, the integrity of which needs to be preserved throughout the lifespan of the cell and in conjunction with cell cycle progression. Preservation of chromosomal structure is important for proper deployment of cell type-specific gene expression programs. Thus, aberrations in the integrity and structure of chromosomes will predictably

    更新日期:2020-07-05
  • Longitudinal increases in somatic mosaicism of the expanded CTG repeat in myotonic dystrophy type 1 are associated with variation in age-at-onset
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-06-30
    Fernando Morales; Melissa Vásquez; Eyleen Corrales; Rebeca Vindas-Smith; Carolina Santamaría-Ulloa; Baili Zhang; Mario Sirito; Marcos R Estecio; Ralf Krahe; Darren G Monckton

    In myotonic dystrophy type 1 (DM1), somatic mosaicism of the (CTG)n repeat expansion is age-dependent, tissue-specific, and expansion-biased. These features contribute toward variation in disease severity and confound genotype to phenotype analyses. To investigate how the (CTG)n repeat expansion changes over time, we collected three longitudinal blood DNA samples separated by 8 to 15 years and used

    更新日期:2020-06-30
  • Pharmacogenomics Meets Precision Cardio-Oncology: Is there synergistic potential?
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-06-30
    Jennifer K Hockings; Jessica A Castrillon; Feixiong Cheng

    An individual’s inherited genetic make-up and acquired genomic variants may account for a significant portion of observable variability in therapy efficacy and toxicity. Pharmacogenomics (PGx) is the concept that treatments can be modified to account for these differences to increase chances of therapeutic efficacy while minimizing risk of adverse effects. This is particularly applicable to oncology

    更新日期:2020-06-30
  • Increased nuclear but not cytoplasmic activities of CELF1 protein leads to muscle wasting.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-05-15
    Diana C Cox,Xiangnan Guan,Zheng Xia,Thomas A Cooper

    mRNA processing is highly regulated during development through changes in RNA-binding protein (RBP) activities. CUG-BP, Elav-like family member 1 (CELF1, also called CUGBP1) is an RBP, the expression of which decreases in skeletal muscle soon after birth. CELF1 regulates multiple nuclear and cytoplasmic RNA processing events. In the nucleus, CELF1 regulates networks of postnatal alternative splicing

    更新日期:2020-06-29
  • Glucocerebrosidase deficiency promotes release of α-synuclein fibrils from cultured neurons.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-05-11
    Matthew E Gegg,Guglielmo Verona,Anthony H V Schapira

    Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the most important genetic risk factor for Parkinson disease (PD). GCase activity is also decreased in sporadic PD brains and with normal ageing. Loss of GCase activity impairs the autophagy lysosomal pathway resulting in increased α-synuclein (α-syn) levels. Furthermore, elevated α-syn results in decreased

    更新日期:2020-06-29
  • Lowe syndrome patient cells display mTOR- and RhoGTPase-dependent phenotypes alleviated by rapamycin and statins.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-05-11
    Kayalvizhi Madhivanan,Swetha Ramadesikan,Wen-Chieh Hsieh,Mariana C Aguilar,Claudia B Hanna,Robert L Bacallao,R Claudio Aguilar

    Lowe syndrome (LS) is an X-linked developmental disease characterized by cognitive deficiencies, bilateral congenital cataracts and renal dysfunction. Unfortunately, this disease leads to the early death of affected children often due to kidney failure. Although this condition was first described in the early 1950s and the affected gene (OCRL1) was identified in the early 1990s, its pathophysiological

    更新日期:2020-06-29
  • Pmp22 Super-enhancer Deletion Causes Tomacula Formation and Conduction Block in Peripheral Nerves.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-04-30
    Harrison Pantera,Bo Hu,Daniel Moiseev,Chris Dunham,Jibraan Rashid,John J Moran,Kathleen Krentz,C Dustin Rubinstein,Seongsik Won,Jun Li,John Svaren

    Copy number variation of the peripheral nerve myelin gene Peripheral Myelin Protein 22 (PMP22) causes multiple forms of inherited peripheral neuropathy. The duplication of a 1.4 Mb segment surrounding this gene in chromosome 17p12 (c17p12) causes the most common form of Charcot-Marie-Tooth disease type 1A, whereas the reciprocal deletion of this gene causes a separate neuropathy termed hereditary neuropathy

    更新日期:2020-06-29
  • Twist1 induces chromosomal instability (CIN) in colorectal cancer cells.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-04-27
    Maithilee Khot,Dyuthi Sreekumar,Sanika Jahagirdar,Apoorva Kulkarni,Kishore Hari,E E Faseela,Radhakrishnan Sabarinathan,Mohit Kumar Jolly,Kundan Sengupta

    Twist1 is a basic helix-loop-helix transcription factor, essential during early development in mammals. While Twist1 induces epithelial-to-mesenchymal transition (EMT), here we show that Twist1 overexpression enhances nuclear and mitotic aberrations. This is accompanied by an increase in whole chromosomal copy number gains and losses, underscoring the role of Twist1 in inducing chromosomal instability

    更新日期:2020-06-29
  • ALS-associated genes in SCA2 mouse spinal cord transcriptomes.
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-04-20
    Daniel R Scoles,Warunee Dansithong,Lance T Pflieger,Sharan Paul,Mandi Gandelman,Karla P Figueroa,Frank Rigo,C Frank Bennett,Stefan M Pulst

    The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the

    更新日期:2020-06-29
  • Temple Syndrome and Kagami-Ogata Syndrome: Clinical Presentations, Genotypes, Models and Mechanisms
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-06-27
    Rexxi Prasasya; Kristen V Grotheer; Linda D Siracusa; Marisa S Bartolomei

    Temple Syndrome (TS) and Kagami-Ogata Syndrome (KOS) are imprinting disorders caused by absence or overexpression of genes within a single imprinted cluster on human chromosome 14q32. TS most frequently arises from maternal UPD14 or epimutations/deletions on the paternal chromosome, whereas KOS most frequently arises from paternal UPD14 or epimutations/deletions on the maternal chromosome. In this

    更新日期:2020-06-27
  • PICALM rescues glutamatergic neurotransmission, behavioural function, and survival in a Drosophila model of Aβ42 toxicity
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-06-27
    Yifan Yu; Teresa Niccoli; Ziyu Ren; Nathaniel S Woodling; Benjamin Aleyakpo; Gyorgy Szabadkai; Linda Partridge

    Alzheimer’s disease (AD) is the most common form of dementia and the most prevalent neurodegenerative disease. Genome Wide Association Studies have linked PICALM to AD risk. PICALM has been implicated in Aβ42 production and turn-over, but whether it plays a direct role in modulating Aβ42 toxicity remains unclear. We found that increased expression of the Drosophila PICALM orthologue lap could rescue

    更新日期:2020-06-27
  • C1orf194 deficiency leads to incomplete early embryonic lethality and dominant intermediate Charcot-Marie-Tooth disease in a knockout mouse model
    Hum. Mol. Genet. (IF 5.1) Pub Date : 2020-06-27
    Cheng Huang; Zong Rui Shen; Jin Huang; Shun Chang Sun; Di Ma; Mei Yi Li; Zhi Kui Wang; Ying Chun Zheng; Zhuo Jun Zheng; Fei He; Xiaoyuan Xu; Ziang Li; Bo Yang Zheng; Yue Mao Li; Xiang Min Xu; Fu Xiong

    Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy, and shows clinical and genetic heterogeneity. Mutations in C1orf194 encoding a Ca2+ regulator in neurons and Schwann cells have been reported previously by us to cause CMT disease. In here, we further investigated the function and pathogenic mechanism of C1or194 by generating C1orf194 knockout (KO) mice. Homozygous

    更新日期:2020-06-27
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