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Human Molecular Genetics

Sébastien Jacquemont, Laura Pacini, Aia E Jønch, Giulia Cencelli, Izabela Rozenberg, Yunsheng He, Laura D'Andrea, Giorgia Pedini, Marwa Eldeeb, Rob Willemsen, Fabrizio Gasparini, Flora Tassone, Randi Hagerman, Baltazar Gomez-Mancilla, Claudia Bagni
No abstract text is available yet for this article.
August 9, 2018: Human Molecular Genetics
Feiran Zhang, Yunhee Kang, Mengli Wang, Yujing Li, Tianlei Xu, Wei Yang, Hongjun Song, Hao Wu, Qiang Shu, Peng Jin
N6-methyladenosine (m6A) is the most prevalent internal modification of mammalian messenger RNAs (mRNAs) and long non-coding RNAs. The biological functions of this reversible RNA modification can be interpreted by cytoplasmic and nuclear "m6A reader" proteins to fine-tune gene expression, such as mRNA degradation and translation initiation. Here we profiled transcriptome-wide m6A sites in adult mouse cerebral cortex, underscoring that m6A is a widespread epitranscriptomic modification in brain. Interestingly, the mRNA targets of fragile X mental retardation protein (FMRP), a selective RNA-binding protein, are enriched for m6A marks...
August 9, 2018: Human Molecular Genetics
Mitsuru Sasaki-Honda, Tatsuya Jonouchi, Meni Arai, Akitsu Hotta, Satomi Mitsuhashi, Ichizo Nishino, Ryoichi Matsuda, Hidetoshi Sakurai
DUX4, the causative gene of facioscapulohumeral muscular dystrophy (FSHD), is ectopically expressed in the skeletal muscle cells of FSHD patients because of chromatin relaxation at 4q35. The diminished heterochromatic state at 4q35 is caused by either large genome contractions (FSHD1) or mutations in genes encoding chromatin regulators, such as SMCHD1 (FSHD2). However, the mechanism by which DUX4 expression is regulated remains largely unknown. Here, using a myocyte model developed from patient-derived induced pluripotent stem cells (iPSCs), we determined that DUX4 expression was increased by oxidative stress (OS), a common environmental stress in skeletal muscle, in both FSHD1 and FSHD2 myocytes...
August 9, 2018: Human Molecular Genetics
Mohamad Karaky, María Fedetz, Victor Potenciano, Eduardo Andrés-León, Anna Esteve Codina, Cristina Barrionuevo, Antonio Alcina, Fuencisla Matesanz
SP140 locus has been associated with multiple sclerosis (MS) as well as other autoimmune diseases by genome-wide association studies (GWAS). The causal variant of these associations (rs28445040-T) alters the splicing of the SP140 gene transcripts reducing the protein expression. We aimed to understand why the reduction of SP140 expression produced by the risk variant can increase the susceptibility to MS. To this end, we determined by RNA-seq analysis the differentially expressed genes after SP140 silencing in lymphoblastoid cell lines (LCLs)...
August 8, 2018: Human Molecular Genetics
Duarte Pólvora-Brandão, Mariana Joaquim, Inês Godinho, Domenico Aprile, Ana Rita Álvaro, Isabel Onofre, Ana Cláudia Raposo, Luís Pereira Almeida, Sofia T Duarte, Simão T Rocha
The human chr15q11-q13 imprinted cluster is linked to several disorders, including Prader-Willi (PWS) and Angelman (AS) syndromes. Recently, disease modelling approaches based on induced pluripotent stem cells (iPSCs) have been used to study these syndromes. A concern regarding the use of these cells for imprinted disease modelling is the numerous imprinting defects found in many iPSCs. Here, by reprogramming skin fibroblasts from a control and an AS individuals, we generated several iPSC lines and addressed the stability of imprinting status across the PWS/AS domain...
August 8, 2018: Human Molecular Genetics
Brittany Whitley, Christina Lam, Hong Cui, Katrina Haude, Renkui Bai, Luis Escobar, Afifa Hamilton, Lauren Brady, Mark A Tarnopolsky, Lauren Dengle, Jonathan Picker, Sharyn Lincoln, Laura L Lackner, Ian A Glass, Suzanne Hoppins
Mitochondrial dynamics, including mitochondrial division, fusion and transport, are integral parts of mitochondrial and cellular function. DNM1L encodes Drp1, a member of the dynamin-related protein family that is required for mitochondrial division. Several de novo mutations in DNM1L are associated with a range of disease states. Here we report the identification of five patients with pathogenic or likely pathogenic variants of DNM1L, including two novel variants. Interestingly, all of the positions identified in these Drp1 variants are fully conserved among all members of the dynamin-related protein family that are involved in membrane division and organelle division events...
August 2, 2018: Human Molecular Genetics
Roberta Sagheddu, Sara Chiappalupi, Laura Salvadori, Francesca Riuzzi, Rosario Donato, Guglielmo Sorci
Duchenne muscular dystrophy (DMD) is a lethal X-linked disease affecting striated muscles, which undergo progressive degeneration and chronic inflammation. RAGE (receptor for advanced glycation end-products), a multiligand receptor involved in myogenesis and inflammation, is absent in healthy adult muscles but is re-expressed in myoblasts, regenerating myofibers and activated immune cells upon acute muscle injury, and in certain myopathies. We show here that RAGE is expressed and chronically stimulated in muscles of mdx mice, an experimental model of DMD, which also release high amounts of the RAGE ligands, HMGB1 and S100B...
August 2, 2018: Human Molecular Genetics
Irantzu Serrano-Mendioroz, Ana Sampedro, Naroa Serna, Rafael Enríquez de Salamanca, Arantza Sanz-Parra, Fernando Corrales, Pedro Berraondo, Oscar Millet, Antonio Fontanellas
A first-in-human gene therapy trial using an adeno-associated viral (AAV) vector for acute intermittent porphyria (AIP) reveals that higher doses would be required to reach therapeutic levels of the porphobilinogen deaminase (PBGD) transgene. We developed a hyperfunctional PBGD protein to improve the therapeutic index without increasing vector dose. A consensus protein sequence from 12 mammal species was compared to the human PBGD sequence, and eight amino acids were selected. I291M and N340S variants showed the highest increase in enzymatic activity when expressed in prokaryotic and eukaryotic systems...
August 1, 2018: Human Molecular Genetics
Tina N Tran, John C Schimenti
Whole exome or genome sequencing is becoming routine in clinical situations for identifying mutations underlying presumed genetic causes of disease, including infertility. While this is a powerful approach for implicating polymorphisms or de novo mutations in genes plausibly related to the phenotype, a greater challenge is to definitively prove causality. This is a crucial requisite for treatment, especially for infertility, in which validation options are limited. In this study, we created a mouse model of a putative infertility allele, DMC1M200V...
August 1, 2018: Human Molecular Genetics
Ken B Hanscombe, David L Morris, Janelle A Noble, Alexander T Dilthey, Philip Tombleson, Kenneth M Kaufman, Mary Comeau, Carl D Langefeld, Marta E Alarcon-Riquelme, Patrick M Gaffney, Chaim O Jacob, Kathy L Sivils, Betty P Tsao, Graciela S Alarcon, Elizabeth E Brown, Jennifer Croker, Jeff Edberg, Gary Gilkeson, Judith A James, Diane L Kamen, Jennifer A Kelly, Joseph McCune, Joan T Merrill, Michelle Petri, Rosalind Ramsey-Goldman, John D Reveille, Jane E Salmon, Hal Scofield, Tammy Utset, Daniel J Wallace, Michael H Weisman, Robert P Kimberly, John B Harley, Cathryn M Lewis, Lindsey A Criswell, Timothy J Vyse
Genetic variation within the major histocompatibility complex contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism, and extensive linkage disequilibrium have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AA) and Europeans (EUR). We observed a greater number of HLA alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, about double the number, 95 per hundred...
July 31, 2018: Human Molecular Genetics
Lin Zhang, Zixi Sun, Peiquan Zhao, Lulin Huang, Mingchun Xu, Yeming Yang, Xue Chen, Fang Lu, Xiang Zhang, Hui Wang, Shanshan Zhang, Wenjing Liu, Zhilin Jiang, Shi Ma, Rui Chen, Chen Zhao, Zhenglin Yang, Ruifang Sui, Xianjun Zhu
Retinitis pigmentosa (RP) is an inheritable retina degenerative disease leading to blindness. Despite the identification of 70 genes associated with RP, the genetic cause of approximately 40% of RP patients remains to be elucidated. Whole exome sequencing was applied on the probands of a RP cohort of 68 unsolved cases to identify candidate genetic mutations. A homozygous missense variant (c.173C > T, p.T58 M) was found in HKDC1 in two unrelated families presenting late-onset retinal degeneration. This variant affects highly conserved amino acid residue and is very rare in several databases and absent in 4000 ethnic-matched controls...
July 31, 2018: Human Molecular Genetics
Xiaoping Huang, Beverly P Wu, Diana Nguyen, Yi-Ting Liu, Melika Marani, Jürgen Hench, Paule Bénit, Vera Kozjak-Pavlovic, Pierre Rustin, Stephan Frank, Derek P Narendra
Mutations in paralogous mitochondrial proteins CHCHD2 and CHCHD10 cause autosomal dominant Parkinson Disease (PD) and Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS/FTD), respectively. Using newly generated CHCHD2, CHCHD10, and CHCHD2/10 double knockout cell lines, we find that the proteins are partially functionally redundant and similarly distributed throughout mitochondrial cristae. Contrary to these parallels, both proteins form heterodimers through a bioenergetically regulated mechanism that relies on key differences in the proteins' stability as well as mutual affinity: CHCHD2 is stabilized by loss of mitochondrial membrane potential; CHCHD10 oligomerization requires CHCHD2...
July 31, 2018: Human Molecular Genetics
Buhm Han, Masato Akiyama, Kyung-Kon Kim, Hyunjung Oh, Hyunchul Choi, Cue Hyunkyu Lee, Seulgi Jung, Ho-Su Lee, Emma E Kim, Seungho Cook, Talin Haritunians, Keiko Yamazaki, Sang Hyoung Park, Byong Duk Ye, Dermot P B McGovern, Motohiro Esaki, Takaaki Kawaguchi, Seik-Soon Khor, Kent D Taylor, Jerome I Rotter, Yasuo Suzuki, Toshiyuki Matsui, Satoshi Motoya, So-Young Bang, Tae-Hwan Kim, Yukihide Momozawa, Yoichiro Kamatani, Katsushi Tokunaga, Michiaki Kubo, Yukinori Okada, Suk-Kyun Yang, Kyuyoung Song
Crohn's disease (CD) and ulcerative colitis (UC) are the major types of chronic inflammatory bowel disease (IBD) characterized by recurring episodes of inflammation of the gastrointestinal tract. Although it is well-established that human leukocyte antigen (HLA) is a major risk factor for IBD, it is yet to be determined which HLA alleles or amino acids drive the risks of CD and UC in Asians. To define the roles of HLA for IBD in Asians, we fine-mapped HLA in 12,568 individuals from Korea and Japan (3,294 CD patients, 1,522 UC patients, and 7,752 controls)...
July 31, 2018: Human Molecular Genetics
Juthaporn Assawachananont, Soo-Young Kim, Koray D Kaya, Robert Fariss, Jerome E Roger, Anand Swaroop
In the mammalian retina, rod and cone photoreceptors transmit the visual information to bipolar neurons through highly-specialized ribbon synapses. We have limited understanding of regulatory pathways that guide morphogenesis and organization of photoreceptor presynaptic architecture in the developing retina. While leucine zipper transcription factor NRL determines rod cell fate and function, cone-rod homeobox (CRX) controls the expression of both rod- and cone-specific genes and is critical for terminal differentiation of photoreceptors...
July 31, 2018: Human Molecular Genetics
Fangyi Gu, Ting-Huei Chen, Ruth M Pfeiffer, Maria Concetta Fargnoli, Donato Calista, Paola Ghiorzo, Ketty Peris, Susana Puig, Chiara Menin, Arcangela De Nicolo, Monica Rodolfo, Cristina Pellegrini, Lorenza Pastorino, Evangelos Evangelou, Tongwu Zhang, Xing Hua, Curt T DellaValle, D Timothy Bishop, Stuart MacGregor, Mark I Iles, Matthew H Law, Anne Cust, Kevin M Brown, Alexander J Stratigos, Eduardo Nagore, Stephen Chanock, Jianxin Shi, Maria Teresa Landi
Melanoma heritability is among the highest for cancer and single nucleotide polymorphisms (SNPs) contribute to it. To date, only SNPs that reached statistical significance in genome-wide association studies or few candidate SNPs have been included in melanoma risk prediction models. We compared four approaches for building polygenic risk scores (PRS) using 12,874 melanoma cases and 23,203 controls from Melanoma Meta-Analysis Consortium as a training set, and newly genotyped 3,102 cases and 2,301 controls from the MelaNostrum consortium for validation...
July 30, 2018: Human Molecular Genetics
Dandi Qiao, Asher Ameli, Dmitry Prokopenko, Han Chen, Alvin T Kho, Margaret M Parker, Jarrett Morrow, Brian D Hobbs, Yanhong Liu, Terri H Beaty, James D Crapo, Kathleen C Barnes, Deborah A Nickerson, Michael Bamshad, Craig P Hersh, David A Lomas, Alvar Agusti, Barry J Make, Peter M A Calverley, Claudio F Donner, Emiel F Wouters, Jørgen Vestbo, Peter D Paré, Robert D Levy, Stephen I Rennard, Ruth Tal-Singer, Margaret R Spitz, Amitabh Sharma, Ingo Ruczinski, Christoph Lange, Edwin K Silverman, Michael H Cho
Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is substantially influenced by genetic factors. Alpha-1 antitrypsin deficiency demonstrates that rare coding variants of large effect can influence COPD susceptibility. To identify additional rare coding variants in patients with severe COPD, we conducted whole exome sequencing analysis in 2,543 subjects from two family-based studies (Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene)...
July 27, 2018: Human Molecular Genetics
Ewa J Mularczyk, Mukti Singh, Alan R F Godwin, Francessco Galli, Neil Humphreys, Antony D Adamson, Aleksandr Mironov, Stuart A Cain, Gerhard Sengle, Ray P Boot-Handford, Giulio Cossu, Cay M Kielty, Clair Baldock
Fibrillin microfibrils are extracellular matrix assemblies that form the template for elastic fibres, endow blood vessels, skin, and other elastic tissues with extensible properties. They also regulate the bioavailability of potent growth factors of the TGF-β superfamily. A Disintegrin And Metalloproteinase with Thrombospondin Motifs (ADAMTS)10 is an essential factor in fibrillin microfibril function. Mutations in fibrillin-1 or ADAMTS10 cause Weill-Marchesani syndrome (WMS) characterised by short stature, eye defects, hypermuscularity and thickened skin...
July 27, 2018: Human Molecular Genetics
Nicolas Vignier, Maria Chatzifrangkeskou, Blanca Morales Rodriguez, Mathias Mericskay, Nathalie Mougenot, Gisèle Bonne, Antoine Muchir
Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is an anatomic and pathologic condition associated with muscle and electrical dysfunction of the heart, often leading to heart failure-related disability. There is currently no specific therapy available for patients that target the molecular pathophysiology of LMNA cardiomyopathy. Recent studies suggested that nicotinamide adenine dinucleotide (NAD+) cellular content could be a critical determinant for heart function...
July 24, 2018: Human Molecular Genetics
Caroline M Gorvin, Morten Frost, Tomas Malinauskas, Treena Cranston, Hannah Boon, Christian Siebold, E Yvonne Jones, Fadil M Hannan, Rajesh V Thakker
The calcium-sensing receptor (CaSR) is a homodimeric G-protein coupled receptor that signals via intracellular calcium (Ca2+i) mobilisation and phosphorylation of extracellular signal-regulated kinase (ERK) to regulate extracellular calcium (Ca2+e) homeostasis. The central importance of the CaSR in Ca2+e homeostasis has been demonstrated by the identification of loss- or gain-of-function CaSR mutations that lead to familial hypocalciuric hypercalcaemia (FHH) or autosomal dominant hypocalcaemia (ADH), respectively...
July 20, 2018: Human Molecular Genetics
Manju Swaroop, Matthew J Brooks, Linn Gieser, Anand Swaroop, Wei Zheng
Mucopolysaccharidosis type I (MPS I) is caused by deficiency of α-L-iduronidase (IDUA), a lysosomal enzyme involved in the breakdown and recycling of glycosaminoglycans (GAGs). Although enzyme replacement therapy is available, the efficacy of the treatment for neuropathic manifestations is limited. To facilitate drug discovery and model disease pathophysiology, we generated neural stem cells (NSCs) from MPS I patient-derived induced pluripotent stem cells (iPSCs). The NSCs exhibited characteristic disease phenotypes with deficiency of α-L-iduronidase (IDUA), accumulation of GAGs and enlargement of lysosomes, in agreement with the severity of clinical subgroups of MPS I...
July 19, 2018: Human Molecular Genetics
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