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Human Molecular Genetics

Wujood Khayat, Anna Hackett, Marie Shaw, Alina Ilie, Tracy Dudding-Byth, Vera M Kalscheuer, Louise Christie, Mark A Corbett, Jane Juusola, Kathryn L Friend, Brian M Kirmse, Jozef Gecz, Michael Field, John Orlowski
We report two unrelated families with multigenerational nonsyndromic intellectual disability segregating with a recurrent de novo missense variant (c.1543C>T:p.Leu515Phe) in the alkali cation/proton exchanger gene SLC9A7 (also commonly referred to as NHE7). SLC9A7 is located on human X chromosome at Xp11.3 and has not yet been associated with a human phenotype. The gene is widely transcribed, but especially abundant in brain, skeletal muscle and various secretory tissues. Within cells, SLC9A7 resides in the Golgi apparatus, with prominent enrichment in the trans-Golgi network (TGN) and post-Golgi vesicles...
October 17, 2018: Human Molecular Genetics
Mattéa J Finelli, Davide Aprile, Enrico Castroflorio, Alexander Jeans, Matteo Moschetta, Lauren Chessum, Matteo T Degiacomi, Julia Grasegger, Alexis Lupien-Meilleur, Andrew Bassett, Elsa Rossignol, Philippe M Campeau, Michael R Bowl, Fabio Benfenati, Anna Fassio, Peter L Oliver
Mutations in the Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 (TBC1D24) gene are associated with a range of inherited neurological disorders, from drug-refractory lethal epileptic encephalopathy and DOORS syndrome (Deafness, Onychodystrophy, Osteodystrophy, mental Retardation, Seizures) to non-syndromic hearing loss. TBC1D24 has been implicated in neuronal transmission and maturation, although the molecular function of the gene and the cause of the apparently complex disease spectrum remain unclear. Importantly, heterozygous TBC1D24 mutation carriers have also been reported with seizures, suggesting that haploinsufficiency for TBC1D24 is significant clinically...
October 17, 2018: Human Molecular Genetics
Jeffrey R Gehlhausen, Eric Hawley, Benjamin Mark Wahle, Yongzheng He, Donna Edwards, Steven D Rhodes, Jacquelyn D Lajiness, Karl Staser, Shi Chen, Xianlin Yang, Jin Yuan, Xiaohong Li, Li Jiang, Abbi Smith, Waylan Bessler, George Sandusky, Anat Stemmer-Rachamimov, Timothy J Stuhlmiller, Steven P Angus, Gary L Johnson, Grzegorz Nalepa, Charles W Yates, D Wade Clapp, Su-Jung Park
Schwannomas are common, highly morbid, and medically untreatable tumors that can arise in patients with germline as well as somatic mutations in NF2. These mutations most commonly result in the loss of function of the NF2 encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells. Here, we identify NF-κB-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis...
October 17, 2018: Human Molecular Genetics
Carmen Oleaga-Quintas, Caroline Deswarte, Marcela Moncada-Vélez, Ayse Metin, Indumathi Krishna Rao, Saliha Kanik-Yüksek, Alejandro Nieto-Patlán, Antoine Guérin, Belgin Gülhan, Savita Murthy, Aslinur Özkaya-Parlakay, Laurent Abel, Rubén Martínez-Barricarte, Rebeca Pérez de Diego, Stéphanie Boisson-Dupuis, Xiao-Fei Kong, Jean-Laurent Casanova, Jacinta Bustamante
No abstract text is available yet for this article.
October 17, 2018: Human Molecular Genetics
HyeIn Jang, Erin Oakley, Marie Forbes-Osborne, Melissa Kesler, Rebecca Norcross, Ann C Morris, Emilia Galperin
The extracellular signal-related kinase 1 and 2 (ERK1/2) pathway is a highly conserved signaling cascade with numerous essential functions in development. The scaffold protein Shoc2 amplifies the activity of the ERK1/2 pathway, and is an essential modulator of a variety of signaling inputs. Germline mutations in Shoc2 are associated with the human developmental disease known as Noonan-like syndrome with loose anagen hair (NSLH). Clinical manifestations of this disease include congenital heart defects, developmental delays, distinctive facial abnormalities, reduced growth and cognitive deficits along with hair anomalies...
October 16, 2018: Human Molecular Genetics
Zhuchi Tu, Hui Zhao, Bang Li, Sen Yan, Lu Wang, Yongjin Tang, Zhujun Li, Dazhang Bai, Caijuan Li, Yinqi Lin, Yuefeng Li, Jianrong Liu, Hao Xu, Xiangyu Guo, Yong-Hui Jiang, Yong Q Zhang, Xiao-Jiang Li
Monogenic mutations in the SHANK3 gene, which encodes a postsynaptic scaffold protein, play a causative role in autism spectrum disorder (ASD). Although a number of mouse models with Shank3 mutations have been valuable for investigating the pathogenesis of ASD, species-dependent differences in behaviors and brain structures post considerable challenges to use small animals to model ASD and to translate experimental therapeutics to the clinic. We have used CRISPR/Cas9 to generate a cynomolgus monkey model by disrupting SHANK3 at exon 6 and 12...
October 16, 2018: Human Molecular Genetics
Xiaoguang Liu, Michaeline Hebron, Wangke Shi, Irina Lonskaya, Charbel E-H Moussa
Ubiquitin specific proteases (USPs) are de-ubiquitinases that control protein ubiquitination cycle. The role of de-ubiquitinases is poorly understood in neurodegenerative diseases. We found that USP13 is overexpressed in post-mortem Parkinson's disease (PD) brain. We investigated whether changes in USP13 levels can affect two molecules, parkin and alpha-synuclein, that are implicated in PD pathogenesis. Parkin is an E3 ubiquitin ligase that is regulated by ubiquitination and targets certain proteins for degradation, and alpha-synuclein may be ubiquitinated and recycled in the normal brain...
October 16, 2018: Human Molecular Genetics
Leo H Wang, Seth D Friedman, Dennis Shaw, Lauren Snider, Chao-Jen Wong, Chris B Budech, Sandra L Poliachik, Nancy E Gove, Leann M Lewis, Amy E Campbell, Richard J F L Lemmers, Silvère M Maarel, Stephen J Tapscott, Rabi N Tawil
Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited disease caused by the epigenetic de-repression of the DUX4 gene, a transcription factor normally repressed in skeletal muscle. As targeted therapies are now possible in FSHD, a better understanding of the relationship between DUX4 activity, muscle pathology and muscle MRI changes are crucial both to understand disease mechanisms and for the design of future clinical trials. Here, we performed MRIs of the lower extremities in 36 individuals with FSHD, followed by needle muscle biopsies in safely accessible muscles...
October 12, 2018: Human Molecular Genetics
Tara E Wood, Joshua Barry, Zhenquin Yang, Carlos Cepeda, Michael S Levine, Michelle Gray
Neuronal and non-neuronal cells express the huntingtin protein, yet neurodegeneration in Huntington's Disease (HD) is largely selective, affecting most prominently striatal medium spiny neurons and cortical pyramidal neurons. Selective toxicity of full-length mutant huntingtin (fl-mHTT) may be due in part to its expression in non-neuronal cells. While studies suggest neuronal-glial interactions are important in HD and fl-mHTT is expressed in astrocytes, it has not been determined whether the expression of fl-mHTT in astrocytes is necessary for HD pathogenesis...
October 12, 2018: Human Molecular Genetics
Nan Yang, Nan Wu, Ling Zhang, Yanxue Zhao, Jiaqi Liu, Xiangyu Liang, Xiaojun Ren, Weiyu Li, Weisheng Chen, Shuangshuang Dong, Sen Zhao, Jiachen Lin, Hang Xiang, Huadan Xue, Lu Chen, Hao Sun, Jianguo Zhang, Jiangang Shi, Shuyang Zhang, Daru Lu, Xiaohui Wu, Li Jin, Jiandong Ding, Guixing Qiu, Zhihong Wu, James R Lupski, Feng Zhang
Congenital vertebral malformations (CVM) are associated with human TBX6 compound inheritance which combines a rare null allele and a common hypomorphic allele at the TBX6 locus. Our previous in vitro evidence suggested that this compound inheritance resulted in a TBX6 gene dosage of less than haploinsufficiency (i.e. < 50%) as a potential mechanism of TBX6-associated CVM. To further investigate this pathogenetic model, we ascertained and collected 108 Chinese CVM cases and found ten (9.3%) of them carried TBX6 null mutations in combination with common hypomorphic variants at the second TBX6 allele...
October 10, 2018: Human Molecular Genetics
Anna Pakula, Angela Lek, Jeffrey Widrick, Hiroaki Mitsuhashi, Katlynn M Bugda Gwilt, Vandana M Gupta, Fedik Rahimov, June Criscione, Yuanfan Zhang, Devin Gibbs, Quinn Murphy, Anusha Manglik, Lillian Mead, Louis Kunkel
Facioscapulohumeral dystrophy Type 1 (FSHD-1) is the most common autosomal dominant form of muscular dystrophy with a prevalence of approximately 1 in 8,000 individuals. It is considered a late-onset form of muscular dystrophy and leads to asymmetric muscle weakness in the facial, scapular, trunk and lower extremities. The prevalent hypothesis on disease pathogenesis is explained by misexpression of a germline, primate specific transcription factor DUX4-fl (double homeo-box 4, full-length isoform) linked to the chromosome 4q35...
October 10, 2018: Human Molecular Genetics
Shannon M Conley, Michael W Stuck, Jamie N Watson, Rahel Zulliger, Justin L Burnett, Muna I Naash
The retinal disease gene peripherin 2 (PRPH2) is essential for the formation of photoreceptor outer segments (OS), where it functions in oligomers with and without its homologue ROM1. However, the precise role of these proteins in OS morphogenesis is not understood. By utilizing a knockin mouse expressing a chimeric protein comprised of the body of Rom1 and the C-terminus of Prph2 (termed RRCT), we find that the Prph2 C-terminus is necessary and sufficient for the initiation of OSs, while OS maturation requires the body of Prph2 and associated large oligomers...
October 10, 2018: Human Molecular Genetics
Linda M Polfus, Laura M Raffield, Marsha M Wheeler, Russell P Tracy, Leslie A Lange, Guillaume Lettre, Amanda Miller, Adolfo Correa, Russell P Bowler, Joshua C Bis, Shabnam Salimi, Nancy Swords Jenny, Nathan Pankratz, Biqi Wang, Michael H Preuss, Lisheng Zhou, Arden Moscati, Girish N Nadkarni, Ruth J F Loos, Xue Zhong, Bingshan Li, Jill M Johnsen, Deborah A Nickerson, Alex P Reiner, Paul L Auer, Nhlbi Trans-Omics For Precision Medicine Consortium
E-selectin mediates the rolling of circulating leukocytes during inflammatory processes. Previous genome-wide association studies (GWAS) in European and Asian individuals have identified the ABO locus associated with E-selectin levels. Using Trans-Omics for Precision Medicine (TOPMed) whole-genome sequencing (WGS) data in 2,249 African Americans (AAs) from the Jackson Heart Study (JHS), we examined genome-wide associations with soluble E-selectin levels. In addition to replicating known signals at ABO, we identified a novel association of a common loss-of-function, missense variant in FUT6 (rs17855739,p...
October 10, 2018: Human Molecular Genetics
Jessica Neville Little, Noelle D Dwyer
Building a cerebral cortex of the proper size involves balancing rates and timing of neural stem cell (NSC) proliferation, neurogenesis and cell death. The cellular mechanisms connecting genetic mutations to brain malformation phenotypes are still poorly understood. Microcephaly may result when NSC divisions are too slow, produce neurons too early or undergo apoptosis but the relative contributions of these cellular mechanisms to various types of microcephaly are not understood. We previously showed that mouse mutants in Kif20b (formerly called Mphosph1, Mpp1 or KRMP1) have small cortices that show elevated apoptosis and defects in maturation of NSC MBs, which mediate cytokinetic abscission...
October 9, 2018: Human Molecular Genetics
Katie B Williams, Karlla W Brigatti, Erik G Puffenberger, Claudia Gonzaga-Jauregui, Laurie B Griffin, Erick D Martinez, Olivia K Wenger, Mark Yoder, Vinay V R Kandula, Michael D Fox, Matthew M Demczko, Laura Poskitt, Katryn N Furuya, Jeffrey G Reid, John D Overton, Aris Baras, Lili Miles, Kadakkal Radhakrishnan, Vincent J Carson, Anthony Antonellis, Robert N Jinks, Kevin A Strauss
Aminoacyl-tRNA synthetases (ARSs) are critical for protein translation. Pathogenic variants of ARSs have been previously associated with peripheral neuropathy and multisystem disease in heterozygotes and homozygotes, respectively. We report seven related children homozygous for a novel mutation in tyrosyl-tRNA synthetase (YARS, c.499C > A, p.Pro167Thr) identified by whole exome sequencing. This variant lies within a highly-conserved interface required for protein homodimerization, an essential step in YARS catalytic function...
October 9, 2018: Human Molecular Genetics
Lidia Tagliafierro, Madison Elena Zamora, Ornit Chiba-Falek
Human induced Pluripotent Stem Cell (hiPSC)-derived models have advanced the study of neurodegenerative diseases, including Parkinson's (PD). While age is the strongest risk factor for these disorders, hiPSC-derived models represent rejuvenated neurons. We developed hiPSC-derived Aged dopaminergic and cholinergic neurons to model PD and related synucleinopathies. Our new method induces aging through a 'semi-natural' process, by passaging multiple times at the Neural Precursor Cell stage, prior to final differentiation...
October 9, 2018: Human Molecular Genetics
Graeme A M Nimmo, Sundararajan Venkatesh, Ashutosh K Pandey, Christian R Marshall, Lili-Naz Hazrati, Susan Blaser, Sohnee Ahmed, Jessie Cameron, Kamalendra Singh, Peter N Ray, Carolyn K Suzuki, Grace Yoon
LonP1 is crucial for maintaining mitochondrial proteostasis and mitigating cell stress. We identified a novel homozygous missense LONP1 variant, c.2282 C > T, (p.Pro761Leu), by whole-exome and Sanger sequencing in two siblings born to healthy consanguineous parents. Both siblings presented with stepwise regression during infancy, profound hypotonia and muscle weakness, severe intellectual disability and progressive cerebellar atrophy on brain imaging. Muscle biopsy revealed the absence of ragged-red fibers, which are often seen in mitochondrial DNA (mtDNA) diseases and other muscle disorders...
October 9, 2018: Human Molecular Genetics
Jonathan Gilley, Paul Mayer, Gang Yu, Michael P Coleman
NMNAT2 is an endogenous axon maintenance factor that preserves axon health by blocking Wallerian-like axon degeneration. Mice lacking NMNAT2 die at birth with severe axon defects in both the PNS and CNS so a complete absence of NMNAT2 in humans is likely to be similarly harmful, but probably rare. However, there is evidence of widespread natural variation in human NMNAT2 mRNA expression so it is important to establish whether reduced levels of NMNAT2 have consequences that impact health. Whilst mice that express reduced levels of NMNAT2, either those heterozygous for a silenced Nmnat2 allele, or compound heterozygous for one silenced and one partially silenced Nmnat2 allele, remain overtly normal into old age, we now report that Nmnat2 compound heterozygote mice present with early and age-dependent peripheral nerve axon defects...
October 9, 2018: Human Molecular Genetics
Simon Guiraud, Benjamin Edwards, Sarah E Squire, Lee Moir, Adam Berg, Arran Babbs, Nesrine Ramadan, Matthew J Wood, Kay E Davies
Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. Constitutive utrophin expression, a structural and functional paralogue of dystrophin, can successfully prevent the dystrophic pathology in the dystrophin-deficient mdx mouse model. In dystrophic muscles, utrophin is increased as part of the repair process and localised at the sarcolemma of regenerating myofibers. The presence of developmental myosin such as embryonic myosin (MyHC-emb) and neonatal (MyHC-neo) represents a useful marker of muscle regeneration and a meaningful indicator of muscle damage which correlates with the clinical severity of milder Becker Muscular dystrophy (BMD) and DMD patients...
October 9, 2018: Human Molecular Genetics
Lokendra Kumar Sharma, Meenakshi Tiwari, Neeraj Kumar Rai, Yidong Bai
Leber's Hereditary Optic Neuropathy (LHON) is a classical mitochondrial disease caused by mutations in the mitochondrial DNA encoding complex I subunits. Oxidative stress associated with complex I defect has been implicated in developing LHON phenotype such as retinal ganglionic cell (RGC) death and loss of vision. However the mechanism of LHON pathogenesis is still not very clear and thus no effective therapies are available till date. Using cybrid models for LHON, we show that autophagy is significantly compromised in cells carrying LHON specific mtDNA mutations, which results in reduced clearance of dysfunctional mitochondria contributing to cell death...
October 9, 2018: Human Molecular Genetics
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