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Human Mutation

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https://www.readbyqxmd.com/read/29159838/eys-mutation-update-in-silico-assessment-of-271-reported-and-26-novel-variants-in-patients-with-retinitis-pigmentosa
#1
Muriël Messchaert, Lonneke Haer-Wigman, Muhammad I Khan, Frans P M Cremers, Rob W J Collin
Mutations in Eyes shut homolog (EYS) are one of the most common causes of autosomal recessive (ar) retinitis pigmentosa (RP), a progressive blinding disorder. The exact function of the EYS protein and the pathogenic mechanisms underlying EYS-associated RP are still poorly understood, which hampers the interpretation of the causality of many EYS variants discovered to date. We collected all reported EYS variants present in 377 arRP index cases published before June 2017, and uploaded them in the Leiden Open Variation Database (www...
November 21, 2017: Human Mutation
https://www.readbyqxmd.com/read/29134705/a-dystroglycan-mutation-p-cys667phe-associated-to-muscle-eye-brain-disease-with-multicystic-leucodystrophy-results-in-er-retention-of-the-mutant-protein
#2
Giulia Signorino, Sonia Covaceuszach, Manuela Bozzi, Wolfgang Hubner, Viola Mönkemöller, Petr V Konarev, Alberto Cassetta, Andrea Brancaccio, Francesca Sciandra
Dystroglycan (DG) is a cell adhesion complex composed by two subunits, the highly glycosylated α-DG and the transmembrane β-DG. In skeletal muscle, DG is involved in dystroglycanopathies, a group of heterogeneous muscular dystrophies characterized by a reduced glycosylation of α-DG. The genes mutated in secondary dystroglycanopathies are involved in the synthesis of O-mannosyl glycans and in the O-mannosylation pathway of α-DG. Mutations in the DG gene (DAG1), causing primary dystroglycanopathies, destabilize the α-DG core protein influencing its binding to modifying enzymes...
November 13, 2017: Human Mutation
https://www.readbyqxmd.com/read/29127725/a-loss-of-function-homozygous-mutation-in-ddx59-implicates-a-conserved-dead-box-rna-helicase-in-nervous-system-development-and-function
#3
Vincenzo Salpietro, Stephanie Efthymiou, Andreea Manole, Bhawana Maurya, Sarah Wiethoff, Balasubramaniem Ashokkumar, Maria Concetta Cutrupi, Valeria Dipasquale, Sara Manti, Juan A Botia, Mina Ryten, Jana Vandrovcova, Oscar D Bello, Conceicao Bettencourt, Kshitij Mankad, Ashim Mukherjee, Mousumi Mutsuddi, Henry Houlden
We report on a homozygous frameshift deletion in DDX59 (c.185del: p.Phe62fs*13) in a family presenting with oro-facio-digital syndrome phenotype associated to a broad neurological involvement characterized by microcephaly, intellectual disability, epilepsy, and white matter signal abnormalities associated with cortical and sub-cortical ischemic events. DDX59 encodes a DEAD-box RNA helicase and its role in brain function and neurological diseases is unclear. We showed a reduction of mutant cDNA and perturbation of SHH signalling from patient-derived cell lines; furthermore, analysis of human brain gene expression provides evidence that DDX59 is enriched in oligodendrocytes and might act within pathways of leukoencephalopathies associated genes...
November 11, 2017: Human Mutation
https://www.readbyqxmd.com/read/29124833/a-nonstop-variant-in-reep1-causes-peripheral-neuropathy-by-unmasking-a-3-utr-encoded-aggregation-inducing-motif
#4
Andrea S Bock, Sven Günther, Julia Mohr, Lisa V Goldberg, Amir Jahic, Cornelia Klisch, Christian A Hübner, Saskia Biskup, Christian Beetz
Single nucleotide variants that abolish the stop codon ('nonstop' alterations) are a unique type of substitution in genomic DNA. Whether they confer instability of the mutant mRNA or result in expression of a C-terminally extended protein depends on the absence or presence of a downstream in-frame stop codon, respectively. Of the predicted protein extensions, only few have been functionally characterized. In a family with autosomal dominant Charcot-Marie-Tooth disease type 2, i.e. an axonopathy affecting sensory neurons as well as lower motor neurons, we identified a heterozygous nonstop variant in REEP1...
November 9, 2017: Human Mutation
https://www.readbyqxmd.com/read/29105242/ercc4-variants-identified-in-a-cohort-of-patients-with-segmental-progeroid-syndromes
#5
Takayasu Mori, Matthew J Yousefzadeh, Maryam Faridounnia, Jessica X Chong, Fuki M Hisama, Louanne Hudgins, Gabriela Mercado, Erin A Wade, Amira S Barghouthy, Lin Lee, George M Martin, Deborah A Nickerson, Michael J Bamshad, Laura J Niedernhofer, Junko Oshima
Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5' incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia...
November 3, 2017: Human Mutation
https://www.readbyqxmd.com/read/29098742/a-comprehensive-approach-to-identification-of-pathogenic-fanca-variants-in-fanconi-anemia-patients-and-their-families
#6
Danielle C Kimble, Francis P Lach, Siobhan Q Gregg, Frank X Donovan, Elizabeth K Flynn, Aparna Kamat, Alice Young, Meghana Vemulapalli, James W Thomas, James C Mullikin, Arleen D Auerbach, Agata Smogorzewska, Settara C Chandrasekharappa
Fanconi anemia (FA) is a rare recessive DNA repair deficiency resulting from mutations in one of at least 22 genes. Two-thirds of FA families harbor mutations in FANCA. To genotype patients in the International Fanconi Anemia Registry (IFAR) we employed multiple methodologies, screening 216 families for FANCA mutations. We describe identification of 57 large deletions and 261 sequence variants, in 159 families. All but seven families harbored distinct combinations of two mutations demonstrating high heterogeneity...
November 2, 2017: Human Mutation
https://www.readbyqxmd.com/read/29098738/urine-derived-podocytes-lineage-cells-a-promising-tool-for-precision-medicine-in-alport-syndrome
#7
S Daga, M Baldassarri, C Lo Rizzo, C Fallerini, V Imperatore, I Longo, E Frullanti, E Landucci, L Massella, C Pecoraro, G Garosi, F Ariani, M A Mencarelli, F Mari, A Renieri, A M Pinto
Alport Syndrome (ATS) is a rare genetic disorder caused by collagen IV genes mutations, leading to Glomerular Basement Membrane (GBM) damage up to end-stage renal disease. Podocytes, the main component of the glomerular structure, are the only cells able to produce all the three collagens IV alpha chains associated to ATS and thus, they are key-players in ATS pathogenesis. However, podocytes-targeted therapeutic strategies, have been hampered by the difficulty of non-invasively isolating them and transcripts-based diagnostic approaches are complicated by the inaccessibility of other COL4 chains-expressing cells...
November 2, 2017: Human Mutation
https://www.readbyqxmd.com/read/29098737/structural-and-functional-differences-in-phox2b-frameshift-mutations-underlie-isolated-or-syndromic-congenital-central-hypoventilation-syndrome
#8
Simona Di Lascio, Roberta Benfante, Eleonora Di Zanni, Silvia Cardani, Annalisa Adamo, Diego Fornasari, Isabella Ceccherini, Tiziana Bachetti
Heterozygous mutations in the PHOX2B gene are causative of Congenital Central Hypoventilation Syndrome (CCHS), a neurocristopathy characterised by defective autonomic control of breathing due to the impaired differentiation of neural crest cells (NCCs). Among PHOX2B mutations, polyalanine (polyAla) expansions are almost exclusively associated with isolated CCHS, whereas frameshift variants, although less frequent, are often more severe than polyAla expansions and identified in syndromic CCHS. This paper provides a complete review of all the frameshift mutations identified in cases of isolated and syndromic CCHS reported in the literature as well as those identified by us and not yet published...
November 2, 2017: Human Mutation
https://www.readbyqxmd.com/read/29068549/expanding-the-genetic-architecture-and-phenotypic-spectrum-in-the-skeletal-ciliopathies
#9
Wenjuan Zhang, S Paige Taylor, Hayley A Ennis, Kimberly N Forlenza, Ivan Duran, Bing Li, Jorge A Ortiz Sanchez, Lisette Nevarez, Deborah A Nickerson, Michael Bamshad, Ralph S Lachman, Deborah Krakow, Daniel H Cohn
Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis van Creveld (EVC) syndrome and cranioectodermal dysplasia (CED) phenotypes...
October 25, 2017: Human Mutation
https://www.readbyqxmd.com/read/29068161/dcc-mutation-update-congenital-mirror-movements-isolated-agenesis-of-the-corpus-callosum-and-developmental-split-brain-syndrome
#10
Ashley Pl Marsh, Timothy J Edwards, Charles Galea, Helen M Cooper, Elizabeth C Engle, Saumya S Jamuar, Aurélie Méneret, Marie-Laure Moutard, Caroline Nava, Agnès Rastetter, Gail Robinson, Guy Rouleau, Emmanuel Roze, Megan Spencer-Smith, Oriane Trouillard, Thierry Billette de Villemeur, Christopher A Walsh, Timothy W Yu, Delphine Heron, Elliott H Sherr, Linda J Richards, Christel Depienne, Richard J Leventer, Paul J Lockhart
The deleted in colorectal cancer (DCC) gene encodes the netrin-1 receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum, or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome...
October 25, 2017: Human Mutation
https://www.readbyqxmd.com/read/29067733/whole-exome-and-whole-genome-sequencing-with-dried-blood-spot-dna-without-whole-genome-amplification
#11
Laia Bassaganyas, George Freedman, Dedeepya Vaka, Eunice Wan, Richard Lao, Flavia Chen, Mark Kvale, Robert J Currier, Jennifer M Puck, Pui-Yan Kwok
Newborn screening for rare conditions is performed in all 50 states in the USA. We have partnered with the California Department of Public Health Genetic Disease Laboratory to determine whether sufficient DNA can be extracted from archived dried blood spots for next generation sequencing in the hopes that next generation sequencing can play a role in newborn screening. We optimized the DNA extraction and sequencing library preparation protocols for residual infant dried blood spots archived over 20 years ago and successfully obtained acceptable whole exome and whole genome sequencing data...
October 25, 2017: Human Mutation
https://www.readbyqxmd.com/read/29064616/gain-of-function-hcn2-variants-in-genetic-epilepsy
#12
Melody Li, Snezana Maljevic, A Marie Phillips, Slave Petrovski, Michael Hildebrand, Rosemary Burgess, Therese Mount, Federico Zara, Pasquale Striano, Julian Schubert, Holger Thiele, Peter Nürnberg, Michael Wong, Judith L Weisenberg, Liu Lin Thio, Holger Lerche, Ingrid E Scheffer, Samuel F Berkovic, Steven Petrou, Christopher A Reid
Genetic generalized epilepsy (GGE) is a common epilepsy syndrome that encompasses seizure disorders characterized by spike-and-wave discharges (SWDs). Pacemaker hyperpolarization-activated cyclic nucleotide-gated channels (HCN) are considered integral to SWD genesis, making them an ideal gene candidate for GGE. We identified HCN2 missense variants from a large cohort of 585 GGE patients, recruited by the Epilepsy Phenome-Genome Project (EPGP), and performed functional analysis using two-electrode voltage clamp recordings from Xenopus oocytes...
October 24, 2017: Human Mutation
https://www.readbyqxmd.com/read/29044887/quantitative-mapping-of-genetic-similarity-in-human-heritable-diseases-by-shared-mutations
#13
Huiying Zhao, Yuedong Yang, Yutong Lu, Matthew Mort, David N Cooper, Zhiyi Zuo, Yaoqi Zhou
Many genetic diseases exhibit considerable epidemiological comorbidity and common symptoms, which provokes debate about the extent of their etiological overlap. The rapid growth in the number of known disease-causing mutations in the Human Gene Mutation Database (HGMD) has allowed us to characterise genetic similarities between diseases by ascertaining the extent to which identical genetic mutations are shared between diseases. Using this approach, we show that 41.6% of disease pairs in all possible pairs (42, 083) exhibit a significant sharing of mutations (P-value < 0...
October 17, 2017: Human Mutation
https://www.readbyqxmd.com/read/29044829/enzyme-replacement-therapy-prevents-loss-of-bone-and-fat-mass-in-murine-homocystinuria
#14
Tomas Majtan, Insun Park, Erez M Bublil, Jan P Kraus
Skeletal and connective tissue defects are the most striking symptoms in patients suffering from classical homocystinuria (HCU). Here, we determined body composition and bone mass in three mouse models of HCU and assessed whether a long-term administration of enzyme replacement therapy (ERT) corrected the phenotype. The mouse models of HCU were analyzed using dual-energy X-ray absorptiometry and the data were complemented by plasma biochemical profiles. Both the mouse model lacking CBS (KO) and the one expressing human CBS mutant transgene on a mouse CBS null background (I278T) showed marked bone loss and decreased weight mostly due to a lower fat content compared with negative controls...
October 16, 2017: Human Mutation
https://www.readbyqxmd.com/read/29044765/a-novel-inborn-error-of-the-coenzyme-q10-biosynthesis-pathway-cerebellar-ataxia-and-static-encephalomyopathy-due-to-coq5-c-methyltransferase-deficiency
#15
May Christine V Malicdan, Thierry Vilboux, Bruria Ben-Zeev, Jennifer Guo, Aviva Eliyahu, Ben Pode-Shakked, Amir Dori, Sravan Kakani, Settara C Chandrasekharappa, Carlos R Ferreira, Natalia Shelestovich, Dina Marek-Yagel, Hadass Pri-Chen, Ilan Blatt, John E Niederhuber, Langping He, Camilo Toro, Robert W Taylor, John Deeken, Tal Yardeni, Douglas C Wallace, William A Gahl, Yair Anikster
Primary coenzyme Q10 (CoQ10 ; MIM# 607426) deficiencies are an emerging group of inherited mitochondrial disorders with heterogonous clinical phenotypes. Over a dozen genes are involved in the biosynthesis of CoQ10 , and mutations in several of these are associated with human disease. However, mutations in COQ5 (MIM# 616359), catalyzing the only C-methylation in the CoQ10 synthetic pathway, have not been implicated in human disease. Here, we report three female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, and cognitive disability...
October 16, 2017: Human Mutation
https://www.readbyqxmd.com/read/29035424/cyp21a2-mutation-update-comprehensive-analysis-of-databases-and-published-genetic-variants
#16
Leandro Simonetti, Carlos D Bruque, Cecilia S Fernández, Belén Benavides-Mori, Marisol Delea, Jorge E Kolomenski, Lucía D Espeche, Noemí D Buzzalino, Alejandro D Nadra, Liliana Dain
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of adrenal steroidogenesis. Disorders in steroid 21-hydroxylation account for over 95% of patients with CAH. Clinically, the 21-hydroxylase deficiency has been classified in a broad spectrum of clinical forms, ranging from severe or classical, to mild late onset or non-classical. Known allelic variants in the disease causing CYP21A2 gene are spread among different sources. Until recently, most variants reported have been identified in the clinical setting, which presumably bias described variants to pathogenic ones, as those found in the CYPAlleles database...
October 16, 2017: Human Mutation
https://www.readbyqxmd.com/read/29034544/cyp2u1-activity-is-altered-by-missense-mutations-in-hereditary-spastic-paraplegia-56
#17
Christelle M Durand, Laura Dhers, Christelle Tesson, Alessandra Tessa, Laetitia Fouillen, Stéphanie Jacqueré, Laure Raymond, Isabelle Coupry, Giovanni Benard, Frédéric Darios, Khalid H El-Hachimi, Guja Astrea, François Rivier, Guillaume Banneau, Claire Pujol, Didier Lacombe, Alexandra Durr, Patrick J Babin, Filippo M Santorelli, Nicolas Pietrancosta, Jean-Luc Boucher, Daniel Mansuy, Giovanni Stevanin, Cyril Goizet
Hereditary Spastic Paraplegia (HSP) is an inherited disorder of the central nervous system mainly characterized by gradual spasticity and weakness of the lower limbs. SPG56 is a rare autosomal recessive early onset complicated form of HSP caused by mutations in CYP2U1. The CYP2U1 enzyme was shown to catalyze the hydroxylation of arachidonic acid. Here, we report two further SPG56 families carrying 3 novel CYP2U1 missense variants and the development of an in vitro biochemical assay to determine the pathogenicity of missense variants of uncertain clinical significance...
October 16, 2017: Human Mutation
https://www.readbyqxmd.com/read/29027717/functional-characterization-of-five-nr5a1-gene-mutations-found-in-patients-with-46-xy-disorders-of-sex-development
#18
Helena Fabbri-Scallet, Maricilda Palandi de Mello, Gil Guerra-Júnior, Andréa Trevas Maciel-Guerra, Juliana Gabriel Ribeiro de Andrade, Camila Maia Costa de Queiroz, Isabella Lopes Monlleó, Dagmar Struve, Olaf Hiort, Ralf Werner
Steroidogenic factor-1 (SF1), encoded by the NR5A1 gene, is a key regulator of steroidogenesis and reproductive development. NR5A1 mutations described in 46,XY patients with disorder of sex development (DSD) can be associated with a range of conditions of phenotypes, however the genotype-phenotype correlation remains elusive in many cases. In the present study, we describe the impact of five NR5A1 variants (three novel: p.Arg39Cys, p.Ser32Asn and p.Lys396Argfs*34; and two previously described: p.Cys65Tyr and p...
October 13, 2017: Human Mutation
https://www.readbyqxmd.com/read/29027299/functional-characterization-of-novel%C3%A2-nr5a1%C3%A2-variants-reveals-multiple-complex-roles-in-disorders-of-sex-development
#19
Gorjana Robevska, Jocelyn A van den Bergen, Thomas Ohnesorg, Stefanie Eggers, Chloe Hanna, Remko Hersmus, Elizabeth M Thompson, Anne Baxendale, Charles F Verge, Antony R Lafferty, Nanis S Marzuki, Ardy Santosa, Nurin A Listyasari, Stefan Riedl, Garry Warne, Leendert Looijenga, Sultana Faradz, Katie L Ayers, Andrew H Sinclair
Variants in the NR5A1 gene encoding SF1 have been described in a diverse spectrum of disorders of sex development (DSD). Recently, we reported the use of a targeted gene panel for DSD where we identified 15 individuals with a variant in NR5A1, nine of which are novel. Here, we examine the functional effect of these changes in relation to the patient phenotype. All novel variants tested had reduced trans-activational activity, while several had altered protein level, localization, or conformation. In addition, we found evidence of new roles for SF1 protein domains including a region within the ligand binding domain that appears to contribute to SF1 regulation of Müllerian development...
October 13, 2017: Human Mutation
https://www.readbyqxmd.com/read/29024177/differential-regulation-of-two-flna-transcripts-explains-some-of-the-phenotypic-heterogeneity-in-the-loss-of-function-filaminopathies
#20
Zandra A Jenkins, Alison Macharg, Cheng-Yee Chang, Margriet van Kogelenberg, Tim Morgan, Sophia Frentz, Wenhua Wei, Jacek Pilch, Mark Hannibal, Nicola Foulds, George McGillivray, Richard J Leventer, Sixto García-Miñaúr, Stuart Sugito, Scott Nightingale, David M Markie, Tracy Dudding, Raj P Kapur, Stephen P Robertson
Loss-of-function mutations in the X-linked gene FLNA can lead to abnormal neuronal migration, vascular and cardiac defects, and congenital intestinal pseudo-obstruction (CIPO), the latter characterized by anomalous intestinal smooth muscle layering. Survival in male hemizygotes for such mutations is dependent on retention of residual FLNA function but it is unclear why a subgroup of males with mutations in the 5' end of the gene can present with CIPO alone. Here, we demonstrate evidence for the presence of two FLNA isoforms differing by 28 residues at the N-terminus initiated at ATG(+1) and ATG(+82) ...
October 12, 2017: Human Mutation
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