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Human Molecular Genetics

Brahim Belbellaa, Laurence Reutenauer, Laurent Monassier, Hélène Puccio
Friedreich Ataxia (FA) is currently an incurable inherited mitochondrial neurodegenerative disease caused by reduced levels of frataxin. Cardiac failure constitutes the main cause of premature death in FA. While AAV-mediated cardiac gene therapy was shown to fully reverse the cardiac and mitochondrial phenotype in mouse models, this was achieved at high dose of vector resulting in the transduction of almost all cardiomyocytes, a dose and biodistribution that is unlikely to be replicated in clinic. The purpose of this study was to define the minimum vector biodistribution corresponding to the therapeutic threshold, at different stages of the disease progression...
December 13, 2018: Human Molecular Genetics
Airong Li, Yang Peng, Lauren M Taiclet, Rudolph E Tanzi
Hidradenitis suppurativa (HS), or acne inversa, is a chronic inflammatory skin disorder characterized clinically with acne-like lesions in apocrine gland-bearing skin, follicular occlusion and recurrent inflammation. Thirty-four unique mutations in patients with HS have been found in three genes encoding the γ-secretase complex: nicastrin (NCSTN), presenilin 1 (PSEN1), presenilin enhancer 2 (PSENEN) and in POGLUT1, an endoplasmic reticulum (ER) O-glucosyltransferase involved in Notch signaling. We have carried out a system review and have performed a functional analysis of the 34 unique reported HS-linked mutations in NCSTN, PSEN1, PSENEN and POGLUT1...
December 13, 2018: Human Molecular Genetics
Keiko Yamamoto, Masanobu Kawai, Miwa Yamazaki, Kanako Tachikawa, Takuo Kubota, Keiichi Ozono, Toshimi Michigami
Natriuretic peptide receptor B (NPRB) produces cyclic guanosine monophosphate (cGMP) when bound by C-type natriuretic peptide (CNP). Activating mutations in NPRB cause a skeletal overgrowth disorder, which has been named epiphyseal chondrodysplasia, Miura type (ECDM; OMIM #615923). Here we explored the cellular and molecular mechanisms for the skeletal overgrowth in ECDM using a mouse model in which an activating mutant NPRB is specifically expressed in chondrocytes. The mutant mice (NPRB[p.V883M]-Tg) exhibited postnatal skeletal overgrowth and increased cGMP in cartilage...
December 13, 2018: Human Molecular Genetics
S Sayols-Baixeras, I Subirana, C Lluis-Ganella, F Civeira, J Roquer, A N Do, D Absher, A Cenarro, D Muñoz, C Soriano-Tárraga, J Jiménez-Conde, J M Ordovas, M Senti, S Aslibekyan, J Marrugat, D K Arnett, R Elosua
No abstract text is available yet for this article.
December 12, 2018: Human Molecular Genetics
Arianna Russo, Raffaella Scardigli, Federico La Regina, Melissa E Murray, Nicla Romano, Dennis W Dickson, Benjamin Wolozin, Antonino Cattaneo, Marcello Ceci
No abstract text is available yet for this article.
December 12, 2018: Human Molecular Genetics
Lies Van Horebeek, Kelly Hilven, Klara Mallants, Annemarie Van Nieuwenhuijze, Tiina Kelkka, Paula Savola, Satu Mustjoki, Susan M Schlenner, Adrian Liston, Bénédicte Dubois, An Goris
The role of somatic variants in diseases beyond cancer is increasingly being recognized, with potential roles in autoinflammatory and autoimmune diseases. However, as mutation rates and allele fractions are lower, studies in these diseases are substantially less tolerant of false positives and bio-informatics algorithms require high replication rates. We developed a pipeline combining two variant callers, MuTect2 and VarScan2, with technical filtering and prioritization. Our pipeline detects somatic variants with allele fractions as low as 0...
December 12, 2018: Human Molecular Genetics
Sophie Belin, Francesca Ornaghi, Ghjuvan'Ghjacumu Shackleford, Jie Wang, Cristina Scapin, Camila Lopez-Anido, Nicholas Silvestri, Neil Robertson, Courtney Williamson, Akihiro Ishii, Carla Taveggia, John Svaren, Rashmi Bansal, H Markus Schwab, Klaus Nave, Pietro Fratta, Maurizio D'Antonio, Yannick Poitelon, M Laura Feltri, Lawrence Wrabetz
Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 type III regulate Schwann cell fate and myelination. Here we ask if modulating neuregulin 1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we improved the myelination defects by early overexpression of neuregulin 1 type III...
December 10, 2018: Human Molecular Genetics
X Raymond Gao, Hua Huang, Heejin Kim
The macula, located near the center of the retina in the human eye, is responsible for providing critical functions, such as central, sharp vision. Structural changes in the macula are associated with many ocular diseases, including age-related macular degeneration (AMD) and glaucoma. Although macular thickness is a highly heritable trait, there are no prior reported genome-wide association studies (GWASs) of it. Here, we describe the first GWAS of macular thickness, which was measured by spectral-domain optical coherence tomography using 68,423 participants from the UK Biobank cohort...
December 7, 2018: Human Molecular Genetics
Stefano Gabriele, Marco Canali, Carla Lintas, Roberto Sacco, Maria Cristina Tirindelli, Arianna Ricciardello, Antonio M Persico
Elevated serotonin (5-HT) blood levels, the first biomarker identified in autism research, has been consistently found in 20-30% of patients with Autism Spectrum Disorder (ASD). Hyperserotonemia is mainly due to greater 5-HT uptake into platelets, mediated by the 5-HT transporter (SERT) located at the platelet plasma membrane. The protein complex involved in platelet SERT trafficking and externalization includes integrin β3, the beta subunit of the platelet membrane adhesive GP IIb/IIIa. Integrin β3 is encoded by the ITGB3 gene, previously identified as a QTL for 5-HT blood levels in ASD at SNP rs2317385...
December 7, 2018: Human Molecular Genetics
Davide Randazzo, Umara Khalique, Joseph J Belanto, Aster Kenea, Dana M Talsness, John T Olthoff, Michelle D Tran, Kristien J Zaal, Katherine Pak, Iago Pinal-Fernandez, Andrew L Mammen, Dan Sackett, James M Ervasti, Evelyn Ralston
In healthy adult skeletal muscle fibers microtubules form a three-dimensional grid-like network. In the mdx mouse, a model of Duchenne muscular dystrophy (DMD), microtubules are mostly disordered, without periodicity. These microtubule defects have been linked to the mdx mouse pathology. We now report that increased expression of the beta 6 class V β-tubulin (tubb6) contributes to the microtubule changes of mdx muscles. Wild-type muscle fibers overexpressing GFP-tubb6 (but not GFP-tubb5) have disorganized microtubules whereas mdx muscle fibers depleted of tubb6 (but not of tubb5) normalize their microtubules, suggesting that increasing tubb6 is toxic...
December 6, 2018: Human Molecular Genetics
Liang Qiang, Emanuela Piermarini, Hemalatha Muralidharan, Wenqian Yu, Lanfranco Leo, Laura E Hennessy, Silvia Fernandes, Theresa Connors, Philip L Yates, Michelle Swift, Lyandysha V Zholudeva, Michael A Lane, Gerardo Morfini, Guillermo M Alexander, Terry D Heiman-Patterson, Peter W Baas
Mutations of the SPAST gene, which encodes the microtubule-severing protein spastin, are the most common cause of Hereditary Spastic Paraplegia. Haploinsufficiency is the prevalent opinion as to the mechanism of the disease, but gain-of-function toxicity of the mutant proteins is another possibility. Here, we report a new transgenic mouse (termed SPASTC448Y mouse) that is not haploinsufficient but expresses human spastin bearing the HSP pathogenic C448Y mutation. Expression of the mutant spastin was documented from fetus to adult, but gait defects reminiscent of Hereditary Spastic Paraplegia (not observed in spastin knockout mice) were adult-onset, as is typical of human patients...
December 6, 2018: Human Molecular Genetics
Patrick Lorès, Charles Coutton, Elma El Khouri, Laurence Stouvenel, Maëlle Givelet, Lucie Thomas, Baptiste Rode, Alain Schmitt, Bruno Louis, Zeinab Sakheli, Marhaba Chaudhry, Angeles Fernandez-Gonzales, Alex Mitsialis, Denis Dacheux, Jean-Philippe Wolf, Jean-François Papon, Gérard Gacon, Estelle Escudier, Christophe Arnoult, Mélanie Bonhivers, Sergey N Savinov, Serge Amselem, Pierre F Ray, Emmanuel Dulioust, Aminata Touré
No abstract text is available yet for this article.
December 5, 2018: Human Molecular Genetics
Jayne Aiken, Jeffrey K Moore, Emily A Bates
The microtubule cytoskeleton supports diverse cellular morphogenesis and migration processes during brain development. Mutations in tubulin genes are associated with severe human brain malformations known as 'tubulinopathies'; however, it is not understood how molecular-level changes in microtubule subunits lead to brain malformations. In this study, we demonstrate that missense mutations affecting arginine at position 402 (R402) of TUBA1A α-tubulin selectively impair dynein motor activity, and severely and dominantly disrupt cortical neuronal migration...
December 4, 2018: Human Molecular Genetics
Alessandra Zanon, Sreehari Kalvakuri, Aleksandar Rakovic, Luisa Foco, Marianna Guida, Christine Schwienbacher, Alice Serafin, Franziska Rudolph, Michaela Trilck, Anne Grünewald, Nancy Stanslowsky, Florian Wegner, Valentina Giorgio, Alexandros A Lavdas, Rolf Bodmer, Peter P Pramstaller, Christine Klein, Andrew A Hicks, Irene Pichler, Seibler Philip
No abstract text is available yet for this article.
November 29, 2018: Human Molecular Genetics
Wei Zhou, Dongrui Ma, Alfred Xuyang Sun, Hoang-Dai Tran, Dong-Liang Ma, Brijesh K Singh, Jin Zhou, Jinyan Zhang, Danlei Wang, Yi Zhao, Paul M Yen, Eyleen Goh, Eng-King Tan
CHCHD2 mutations were linked with autosomal dominant Parkinson's disease (PD) and recently, Alzheimer's disease/ Frontotemporal dementia. In current study, we generated isogenic human stem cell (hESC) lines harboring PD-associated CHCHD2 mutation R145Q or Q126X via CRISPR-Cas9 method, aiming to unravel pathophysiologic mechanism and seek potential intervention strategy against CHCHD2 mutant-caused defects. By engaging super resolution microscopy, we identified a physical proximity and similar distribution pattern of CHCHD2 along mitochondria with MICOS (mitochondrial inner membrane organizing system), a large protein complex maintaining mitochondria cristae...
November 29, 2018: Human Molecular Genetics
Bradley Peter, Geraldine Farge, Carlos Pardo-Hernandez, Stefan Tångefjord, Maria Falkenberg
TWINKLE is the helicase involved in replication and maintenance of mitochondrial DNA (mtDNA) in mammalian cells. Structurally, TWINKLE is closely related to the bacteriophage T7 gp4 protein and comprises a helicase and primase domain joined by a flexible linker region. Mutations in and around this linker region are responsible for autosomal dominant progressive external ophthalmoplegia (adPEO), a neuromuscular disorder associated with deletions in mtDNA. The underlying molecular basis of adPEO-causing mutations remains unclear, but defects in TWINKLE oligomerisation are thought to play a major role...
November 29, 2018: Human Molecular Genetics
Marialetizia Motta, Miray Fidan, Emanuele Bellacchio, Francesca Pantaleoni, Konstantin Schneider-Heieck, Simona Coppola, Guntram Borck, Leonardo Salviati, Martin Zenker, Ion C Cirstea, Marco Tartaglia
Noonan syndrome (NS), the most common RASopathy, is caused by mutations affecting signaling through RAS and the MAPK cascade. Recently, genome scanning has discovered novel genes implicated in NS, whose function in RAS-MAPK signaling remains obscure, suggesting the existence of unrecognized circuits contributing to signal modulation in this pathway. Among these genes, LZTR1 encodes a functionally poorly characterized member of the BTB/POZ protein superfamily. Two classes of germline LZTR1 mutations underlie dominant and recessive forms of NS, while constitutional monoallelic, mostly inactivating, mutations in the same gene cause schwannomatosis, a cancer-prone disorder clinically distinct from NS...
November 27, 2018: Human Molecular Genetics
Cristina Scapin, Cinzia Ferri, Emanuela Pettinato, Desiree Zambroni, Francesca Bianchi, Ubaldo Del Carro, Sophie Belin, Donatella Caruso, Nico Mitro, Marta Pellegatta, Carla Taveggia, Markus H Schwab, Klaus-Armin Nave, M Laura Feltri, Lawrence Wrabetz, Maurizio D'Antonio
Charcot-Marie-Tooth neuropathies (CMTs) are a group of genetic disorders that affect the peripheral nervous system (PNS) with heterogeneous pathogenesis and no available treatment. Axonal Neuregulin 1 type III (Nrg1TIII) drives peripheral nerve myelination by activating downstream signaling pathways such as PI3K/Akt and MAPK/Erk that converge on master transcriptional regulators of myelin genes, such as Krox20. We reasoned that modulating Nrg1TIII activity may constitute a general therapeutic strategy to treat CMTs that are characterized by reduced levels of myelination...
November 27, 2018: Human Molecular Genetics
Kimberly K Long, Karen M O'Shea, Ramzi J Khairallah, Kelly Howell, Sergey Paushkin, Karen S Chen, Shaun M Cote, Micah T Webster, Joseph P Stains, Erin Treece, Alan Buckler, Adriana Donovan
Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of α-motor neurons, leading to profound skeletal muscle atrophy. Patients also suffer from decreased bone mineral density and increased fracture risk. The majority of treatments for SMA, approved or in clinic trials, focus on addressing the underlying cause of disease, insufficient production of full-length SMN protein. While restoration of SMN has resulted in improvements in functional measures, significant deficits remain in both mice and SMA patients following treatment...
November 27, 2018: Human Molecular Genetics
Muhammad Ansar, Sohail Aziz Paracha, Alessandro Serretti, Muhammad T Sarwar, Jamshed Khan, Emmanuelle Ranza, Emilie Falconnet, Justyna Iwaszkiewicz, Sayyed Fahim Shah, Azhar Ali Qaisar, Federico A Santoni, Vincent Zoete, Andre Megarbane, Jawad Ahmed, Roberto Colombo, Periklis Makrythanasis, Stylianos E Antonarakis
FBXL3 (F-Box and Leucine Rich Repeat Protein 3) encodes a protein that contains an F-box and several tandem leucine-rich repeats (LRR) domains. FBXL3 is part of the SCF (Skp1-Cullin-F box protein) ubiquitin ligase complex that binds and leads to phosphorylation dependent degradation of the central clock protein cryptochromes (CRY1 and CRY2) by the proteasome and its absence causes circadian phenotypes in mice and behavioral problems. No FBXL3 related phenotypes have been described in humans. By a combination of exome sequencing and homozygosity mapping, we analyzed two consanguineous families with intellectual disability and identified homozygous LoF (loss-of-function) variants in FBXL3...
November 26, 2018: Human Molecular Genetics
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