Serum gamma-glutamyl transferase and risk of type 2 diabetes in the general Korean population: a Mendelian randomization study
Elevated gamma-glutamyl transferase (GGT) levels are associated with higher risk of type 2 diabetes in observational studies, but the underlying causal relationship is still unclear. Here, we tested a hypothesis that GGT levels have a causal effect on type 2 diabetes risk using Mendelian randomization. Data were collected from 7640 participants in a South Korean population. In a single instrumental variable (IV) analysis using two stage least squares regression with the rs4820599 in the GGT1 gene region as an instrument, one unit of GGT levels (IU/L) was associated with 11% higher risk of type 2 diabetes (odds ratio (OR) =...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Lee, Y. S., Cho, Y., Burgess, S., Davey Smith, G., Relton, C. L., Shin, S.-Y., Shin, M.-J. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research

Identification of genetic modifiers of age-at-onset for familial Parkinsons disease
Parkinson’s disease (PD) is the most common cause of neurodegenerative movement disorder and the second most common cause of dementia. Genes are thought to have a stronger effect on age-at-onset of PD than on risk, yet there has been a phenomenal success in identifying risk loci but not age-at-onset modifiers. We conducted a genome-wide study for age-at-onset. We analysed familial and non-familial PD separately, per prior evidence for strong genetic effect on age-at-onset in familial PD. GWAS was conducted in 431 unrelated PD individuals with at least one affected relative (familial PD) and 1544 non-familial PD from ...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Hill-Burns, E. M., Ross, O. A., Wissemann, W. T., Soto-Ortolaza, A. I., Zareparsi, S., Siuda, J., Lynch, T., Wszolek, Z. K., Silburn, P. A., Mellick, G. D., Ritz, B., Scherzer, C. R., Zabetian, C. P., Factor, S. A., Breheny, P. J., Payami, H. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research

The progressive ankylosis protein ANK facilitates clathrin- and adaptor-mediated membrane traffic at the trans-Golgi network-to-endosome interface
Dominant or recessive mutations in the progressive ankylosis gene ANKH have been linked to familial chondrocalcinosis (CCAL2), craniometaphyseal dysplasia (CMD), mental retardation, deafness and ankylosis syndrome (MRDA). The function of the encoded membrane protein ANK in cellular compartments other than the plasma membrane is unknown. Here, we show that ANK localizes to the trans-Golgi network (TGN), clathrin-coated vesicles and the plasma membrane. ANK functionally interacts with clathrin and clathrin associated adaptor protein (AP) complexes as loss of either protein causes ANK dispersion from the TGN to cytoplasmic en...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Seifert, W., Posor, Y., Schu, P., Stenbeck, G., Mundlos, S., Klaassen, S., Nürnberg, P., Haucke, V., Kornak, U., Kühnisch, J. Tags: ARTICLES Source Type: research

SHOC2 subcellular shuttling requires the KEKE motif-rich region and N-terminal leucine-rich repeat domain and impacts on ERK signalling
SHOC2 is a scaffold protein composed almost entirely by leucine-rich repeats (LRRs) and having an N-terminal region enriched in alternating lysine and glutamate/aspartate residues (KEKE motifs). SHOC2 acts as a positive modulator of the RAS-RAF-MEK-ERK signalling cascade by favouring stable RAF1 interaction with RAS. We previously reported that the p.Ser2Gly substitution in SHOC2 underlies Mazzanti syndrome, a RASopathy clinically overlapping Noonan syndrome, promoting N-myristoylation and constitutive targeting of the mutant to the plasma membrane. We also documented transient nuclear translocation of wild-type SHOC2 upon...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Motta, M., Chillemi, G., Fodale, V., Cecchetti, S., Coppola, S., Stipo, S., Cordeddu, V., Macioce, P., Gelb, B. D., Tartaglia, M. Tags: ARTICLES Source Type: research

Lack of P4H-TM in mice results in age-related retinal and renal alterations
Age-related macular degeneration (AMD), affecting the retinal pigment epithelium (RPE), is the leading cause of blindness in middle-aged and older people in developed countries. Genetic and environmental risk factors have been identified, but no effective cure exists. Using a mouse model we show that a transmembrane prolyl 4-hydroxylase (P4H-TM), which participates in the oxygen-dependent regulation of the hypoxia-inducible factor (HIF), is a potential novel candidate gene for AMD. We show that P4h-tm had its highest expression levels in the mouse RPE and brain, heart, lung, skeletal muscle and kidney. P4h-tm-/- mice were ...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Leinonen, H., Rossi, M., Salo, A. M., Tiainen, P., Hyvärinen, J., Pitkänen, M., Sormunen, R., Miinalainen, I., Zhang, C., Soininen, R., Kivirikko, K. I., Koskelainen, A., Tanila, H., Myllyharju, J., Koivunen, P. Tags: ARTICLES Source Type: research

Muscle dysfunction caused by loss of Magel2 in a mouse model of Prader-Willi and Schaaf-Yang syndromes
Prader-Willi syndrome is characterized by severe hypotonia in infancy, with decreased lean mass and increased fat mass in childhood followed by severe hyperphagia and consequent obesity. Scoliosis and other orthopaedic manifestations of hypotonia are common in children with Prader-Willi syndrome and cause significant morbidity. The relationships among hypotonia, reduced muscle mass and scoliosis have been difficult to establish. Inactivating mutations in one Prader-Willi syndrome candidate gene, MAGEL2, cause a Prader-Willi-like syndrome called Schaaf-Yang syndrome, highlighting the importance of loss of MAGEL2 in Prader-W...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Kamaludin, A. A., Smolarchuk, C., Bischof, J. M., Eggert, R., Greer, J. J., Ren, J., Lee, J. J., Yokota, T., Berry, F. B., Wevrick, R. Tags: ARTICLES Source Type: research

Progressive development of renal cysts in glycogen storage disease type I
In conclusion, renal pathology in GSDI is characterized by progressive tubular dysfunction and the development of polycystic kidneys that probably leads to the development of irreversible renal failure in the late stages. Systematic observations of cyst development by kidney imaging should improve the evaluation of the disease’s progression, independently of biochemical markers. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Gjorgjieva, M., Raffin, M., Duchampt, A., Perry, A., Stefanutti, A., Brevet, M., Tortereau, A., Dubourg, L., Hubert-Buron, A., Mabille, M., Pelissou, C., Lassalle, L., Labrune, P., Mithieux, G., Rajas, F. Tags: ARTICLES Source Type: research

Neuromuscular junctions are pathological but not denervated in two mouse models of spinal bulbar muscular atrophy
Spinal bulbar muscular atrophy (SBMA) is a progressive, late onset neuromuscular disease causing motor dysfunction in men. While the morphology of the neuromuscular junction (NMJ) is typically affected by neuromuscular disease, whether NMJs in SBMA are similarly affected by disease is not known. Such information will shed light on whether defective NMJs might contribute to the loss of motor function and represent a potential therapeutic target for treating symptoms of SBMA. To address this gap in information, the morphology of NMJs was examined in two mouse models of SBMA, a myogenic model that overexpresses wildtype andro...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Poort, J. E., Rheuben, M. B., Breedlove, S. M., Jordan, C. L. Tags: ARTICLES Source Type: research

Variant discovery and breakpoint region prediction for studying the human 22q11.2 deletion using BAC clone and whole genome sequencing analysis
In this study, we sequenced 13 BAC clones derived from LCR22A/D and aligned them with 15 previously available BAC sequences to create a new genetic variation map. The thousands of variants identified by this analysis were not uniformly distributed in the two LCR22s. Moreover, shared single nucleotide variants between LCR22A and LCR22D were enriched in the Breakpoint Cluster Region pseudogene (BCRP) block, suggesting the existence of a possible recombination hotspot there. Interestingly, breakpoints for atypical 22q11.2 rearrangements have previously been located to BCRPs. To further explore this finding, we carried out in-...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Guo, X., Delio, M., Haque, N., Castellanos, R., Hestand, M. S., Vermeesch, J. R., Morrow, B. E., Zheng, D. Tags: ARTICLES Source Type: research

Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling
Distal hereditary motor neuropathies (dHMNs) are clinically and genetically heterogeneous neurological conditions characterized by degeneration of the lower motor neurons. So far, 18 dHMN genes have been identified, however, about 80% of dHMN cases remain without a molecular diagnosis. By a combination of autozygosity mapping, identity-by-descent segment detection and whole-exome sequencing approaches, we identified two novel homozygous mutations in the SIGMAR1 gene (p.E138Q and p.E150K) in two distinct Italian families affected by an autosomal recessive form of HMN. Functional analyses in several neuronal cell lines stron...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Gregianin, E., Pallafacchina, G., Zanin, S., Crippa, V., Rusmini, P., Poletti, A., Fang, M., Li, Z., Diano, L., Petrucci, A., Lispi, L., Cavallaro, T., Fabrizi, G. M., Muglia, M., Boaretto, F., Vettori, A., Rizzuto, R., Mostacciuolo, M. L., Vazza, G. Tags: ARTICLES Source Type: research

Calcium dynamics change in degenerating cone photoreceptors
Cone photoreceptors (cones) are essential for high-resolution daylight vision and colour perception. Loss of cones in hereditary retinal diseases has a dramatic impact on human vision. The mechanisms underlying cone death are poorly understood, and consequently, there are no treatments available. Previous studies suggest a central role for calcium (Ca2+) homeostasis deficits in photoreceptor degeneration; however, direct evidence for this is scarce and physiological measurements of Ca2+ in degenerating mammalian cones are lacking. Here, we took advantage of the transgenic HR2.1:TN-XL mouse line that expresses a genetically...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Kulkarni, M., Trifunovic, D., Schubert, T., Euler, T., Paquet-Durand, F. Tags: ARTICLES Source Type: research

Parent-of-origin tumourigenesis is mediated by an essential imprinted modifier in SDHD-linked paragangliomas: SLC22A18 and CDKN1C are candidate tumour modifiers
Mutations in SDHD and SDHAF2 (both located on chromosome 11) give rise to hereditary paraganglioma almost exclusively after paternal transmission of the mutation, and tumours often show loss of the entire maternal copy of chromosome 11. The ‘Hensen’ model postulates that a tumour modifier gene located on chromosome 11p15, a region known to harbour a cluster of imprinted genes, is essential to tumour formation. We observed decreased protein expression of the 11p15 candidate genes CDKN1C, SLC22A18 and ZNF215 evaluated in 60 SDHD-mutated tumours compared to normal carotid body tissue and non-SDH mutant tumours. We...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Hoekstra, A. S., Addie, R. D., Ras, C., Seifar, R. M., Ruivenkamp, C. A., Briaire-de Bruijn, I. H., Hes, F. J., Jansen, J. C., Corssmit, E. P. M., Corver, W. E., Morreau, H., Bovee, J. V. M. G., Bayley, J.-P., Devilee, P. Tags: ARTICLES Source Type: research

Coordinated movement, neuromuscular synaptogenesis and trans-synaptic signaling defects in Drosophila galactosemia models
The multiple galactosemia disease states manifest long-term neurological symptoms. Galactosemia I results from loss of galactose-1-phosphate uridyltransferase (GALT), which converts galactose-1-phosphate + UDP-glucose to glucose-1-phosphate + UDP-galactose. Galactosemia II results from loss of galactokinase (GALK), phosphorylating galactose to galactose-1-phosphate. Galactosemia III results from the loss of UDP-galactose 4’-epimerase (GALE), which interconverts UDP-galactose and UDP-glucose, as well as UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. UDP-glucose pyrophosphorylase (UGP) alternatively makes UDP-g...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Jumbo-Lucioni, P. P., Parkinson, W. M., Kopke, D. L., Broadie, K. Tags: ARTICLES Source Type: research

Sustained expression of FMR1 mRNA from reactivated fragile X syndrome alleles after treatment with small molecules that prevent trimethylation of H3K27
Expansion of a CGG-repeat tract in the 5’-untranslated region of the FMR1 gene to>200 repeats results in epigenetic silencing of the gene by a mechanism that is still unknown. FMR1 gene silencing results in fragile X syndrome (FXS), the most common heritable cause of intellectual disability. We have previously shown that reactivation of the FMR1 gene in FXS cells with 5-azadeoxycytidine (AZA) leads to the transient recruitment of EZH2, the polycomb repressive complex 2 (PRC2) component responsible for H3K27 trimethylation, and that this recruitment depends on the presence of the FMR1 transcript. However, whether H...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Kumari, D., Usdin, K. Tags: ARTICLES Source Type: research

Molecular disturbance underlies to arrhythmogenic cardiomyopathy induced by transgene content, age and exercise in a truncated PKP2 mouse model
Arrhythmogenic cardiomyopathy (ACM) is a disorder characterized by a progressive ventricular myocardial replacement by fat and fibrosis, which lead to ventricular arrhythmias and sudden cardiac death. Mutations in the desmosomal gene Plakophilin-2 (PKP2) accounts for>40% of all known mutations, generally causing a truncated protein. In a PKP2-truncated mouse model, we hypothesize that content of transgene, endurance training and aging will be determinant in disease progression. In addition, we investigated the molecular defects associated with the phenotype in this model. We developed a transgenic mouse model containing...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Moncayo-Arlandi, J., Guasch, E., Sanz-de la Garza, M., Casado, M., Garcia, N. A., Mont, L., Sitges, M., Knöll, R., Buyandelger, B., Campuzano, O., Diez-Juan, A., Brugada, R. Tags: ARTICLES Source Type: research

An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes
Huntington disease (HD) model mice with heterozygous knock-in (KI) of an expanded CAG tract in exon 1 of the mouse huntingtin (Htt) gene homolog genetically recapitulate the mutation that causes HD, and might be favoured for preclinical studies. However, historically these mice have failed to phenotypically recapitulate the human disease. Thus, homozygous KI mice, which lack wildtype Htt, and are much less relevant to human HD, have been used. The zQ175 model was the first KI mouse to exhibit significant HD-like phenotypes when heterozygous. In an effort to exacerbate HD-like phenotypes and enhance preclinical utility, we ...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Southwell, A. L., Smith-Dijak, A., Kay, C., Sepers, M., Villanueva, E. B., Parsons, M. P., Xie, Y., Anderson, L., Felczak, B., Waltl, S., Ko, S., Cheung, D., Dal Cengio, L., Slama, R., Petoukhov, E., Raymond, L. A., Hayden, M. R. Tags: ARTICLES Source Type: research

Dystrophin contains multiple independent membrane-binding domains
Dystrophin is a large sub-sarcolemmal protein. Its absence leads to Duchenne muscular dystrophy (DMD). Binding to the sarcolemma is essential for dystrophin to protect muscle from contraction-induced injury. It has long been thought that membrane binding of dystrophin depends on its cysteine-rich (CR) domain. Here, we provide in vivo evidence suggesting that dystrophin contains three additional membrane-binding domains including spectrin-like repeats (R)1-3, R10-12 and C-terminus (CT). To systematically study dystrophin membrane binding, we split full-length dystrophin into ten fragments and examined subcellular localizati...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Zhao, J., Kodippili, K., Yue, Y., Hakim, C. H., Wasala, L., Pan, X., Zhang, K., Yang, N. N., Duan, D., Lai, Y. Tags: ARTICLES Source Type: research

Table of Contents
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research

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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research

Editorial Board
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research

Front Cover
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research

Intergenic GWAS SNPs are key components of the spatial and regulatory network for human growth
Meta-analysis of genome-wide association studies has resulted in the identification of hundreds of genetic variants associated with growth and stature. Determining how these genetic variants influence growth is important, but most are non-coding, and there is little understanding of how these variants contribute to adult height. To determine the mechanisms by which human variation contributes to growth, we combined spatial genomic connectivity (high-throughput conformation capture) with functional (gene expression, expression Quantitative Trait Loci) data to determine how non-genic loci associated with infant length, puber...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Schierding, W., Antony, J., Cutfield, W. S., Horsfield, J. A., OSullivan, J. M. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research

A transgenic mouse expressing CHMP2Bintron5 mutant in neurons develops histological and behavioural features of amyotrophic lateral sclerosis and frontotemporal dementia
Mutations in the charged multivesicular body protein 2B (CHMP2B) are associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and with a mixed ALS–FTD syndrome. To model this syndrome, we generated a transgenic mouse line expressing the human CHMP2Bintron5 mutant in a neuron-specific manner. These mice developed a dose-dependent disease phenotype. A longitudinal study revealed progressive gait abnormalities, reduced muscle strength and decreased motor coordination. CHMP2Bintron5 mice died due to generalized paralysis. When paralyzed, signs of denervation were present as attested by altered ...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Vernay, A., Therreau, L., Blot, B., Risson, V., Dirrig-Grosch, S., Waegaert, R., Lequeu, T., Sellal, F., Schaeffer, L., Sadoul, R., Loeffler, J.-P., Rene, F. Tags: ARTICLES Source Type: research

Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by a selective loss of motor neurons in the brain and spinal cord. Multiple toxicity pathways, such as oxidative stress, misfolded protein accumulation, and dysfunctional autophagy, are implicated in the pathogenesis of ALS. However, the molecular basis of the interplay between such multiple factors in vivo remains unclear. Here, we report that two independent ALS-linked autophagy-associated gene products; SQSTM1/p62 and ALS2/alsin, but not antioxidant-related factor; NFE2L2/Nrf2, are implicated in the pathogenesis in mutant SOD1 transg...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Hadano, S., Mitsui, S., Pan, L., Otomo, A., Kubo, M., Sato, K., Ono, S., Onodera, W., Abe, K., Chen, X., Koike, M., Uchiyama, Y., Aoki, M., Warabi, E., Yamamoto, M., Ishii, T., Yanagawa, T., Shang, H.-F., Yoshii, F. Tags: ARTICLES Source Type: research

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats
Since the identification of MECP2 as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this disease. The use of additional mammalian RTT models offers the promise of further elucidating critical early mechanisms of disease as well as providing new avenues for translational studies. We have identified significant abnormalities in growth as well as motor and behavioural function in a novel zinc-finger nuclease model of RTT utilizing both male and female rats throughout development. Male rats lacking MeCP2 (Mecp2ZFN/y) were noticeably s...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Patterson, K. C., Hawkins, V. E., Arps, K. M., Mulkey, D. K., Olsen, M. L. Tags: ARTICLES Source Type: research

Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome
Mouse models of the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) have advanced our understanding of Rett syndrome (RTT). RTT is a ‘prototypical’ neurodevelopmental disorder with many clinical features overlapping with other intellectual and developmental disabilities (IDD). Therapeutic interventions for RTT may therefore have broader applications. However, the reliance on the laboratory mouse to identify viable therapies for the human condition may present challenges in translating findings from the bench to the clinic. In addition, the need to identify outcome measures in well-chosen animal m...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Veeraragavan, S., Wan, Y.-W., Connolly, D. R., Hamilton, S. M., Ward, C. S., Soriano, S., Pitcher, M. R., McGraw, C. M., Huang, S. G., Green, J. R., Yuva, L. A., Liang, A. J., Neul, J. L., Yasui, D. H., LaSalle, J. M., Liu, Z., Paylor, R., Samaco, R. C. Tags: ARTICLES Source Type: research

FANCD2 limits BLM-dependent telomere instability in the alternative lengthening of telomeres pathway
Fanconi anemia and Bloom syndrome are genomic instability syndromes caused by mutations in proteins that participate in overlapping DNA repair and replication pathways. Here, we show that the monoubiquitinated form of the Fanconi Anemia protein FANCD2 acts in opposition to the BLM DNA helicase to restrain telomere replication and recombination in human cells that utilize the Alternative Lengthening of Telomeres (ALT) pathway. ALT relies on exchanges of telomeric DNA to maintain telomeres, a process that we show FANCD2 suppresses. Depletion of FANCD2 results in a hyper-ALT phenotype, including an increase in extrachromosoma...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Root, H., Larsen, A., Komosa, M., Al-Azri, F., Li, R., Bazett-Jones, D. P., Stephen Meyn, M. Tags: ARTICLES Source Type: research

Improved imputation accuracy in Hispanic/Latino populations with larger and more diverse reference panels: applications in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Imputation is commonly used in genome-wide association studies to expand the set of genetic variants available for analysis. Larger and more diverse reference panels, such as the final Phase 3 of the 1000 Genomes Project, hold promise for improving imputation accuracy in genetically diverse populations such as Hispanics/Latinos in the USA. Here, we sought to empirically evaluate imputation accuracy when imputing to a 1000 Genomes Phase 3 versus a Phase 1 reference, using participants from the Hispanic Community Health Study/Study of Latinos. Our assessments included calculating the correlation between imputed and observed ...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Nelson, S. C., Stilp, A. M., Papanicolaou, G. J., Taylor, K. D., Rotter, J. I., Thornton, T. A., Laurie, C. C. Tags: ARTICLES Source Type: research

A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay
The neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is caused by loss of function of sacsin, a modular protein that is required for normal mitochondrial network organization. To further understand cellular consequences of loss of sacsin, we performed microarray analyses in sacsin knockdown cells and ARSACS patient fibroblasts. This identified altered transcript levels for oxidative phosphorylation and oxidative stress genes. These changes in mitochondrial gene networks were validated by quantitative reverse transcription PCR. Functional impairment of oxidative phosphorylation wa...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Bradshaw, T. Y., Romano, L. E. L., Duncan, E. J., Nethisinghe, S., Abeti, R., Michael, G. J., Giunti, P., Vermeer, S., Chapple, J. P. Tags: ARTICLES Source Type: research

Cyclooxygenase-2 deficiency impairs muscle-derived stem cell-mediated bone regeneration via cellular autonomous and non-autonomous mechanisms
This study investigated the role of cyclooxygenase-2 (COX-2) expression by donor and host cells in muscle-derived stem cell (MDSC)-mediated bone regeneration utilizing a critical size calvarial defect model. We found that BMP4/green fluorescent protein (GFP)-transduced MDSCs formed significantly less bone in COX-2 knock-out (Cox-2KO) than in COX-2 wild-type (WT) mice. BMP4/GFP-transduced Cox-2KO MDSCs also formed significantly less bone than transduced WT MDSCs when transplanted into calvarial defects created in CD-1 nude mice. The impaired bone regeneration in the Cox-2KO MDSCBMP4/GFP group is associated with downregulati...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Gao, X., Usas, A., Lu, A., Kozemchak, A., Tang, Y., Poddar, M., Sun, X., Cummins, J. H., Huard, J. Tags: ARTICLES Source Type: research

Loss of Magel2 impairs the development of hypothalamic Anorexigenic circuits
Prader–Willi syndrome (PWS) is a genetic disorder characterized by a variety of physiological and behavioral dysregulations, including hyperphagia, a condition that can lead to life-threatening obesity. Feeding behavior is a highly complex process with multiple feedback loops that involve both peripheral and central systems. The arcuate nucleus of the hypothalamus (ARH) is critical for the regulation of homeostatic processes including feeding, and this nucleus develops during neonatal life under of the influence of both environmental and genetic factors. Although much attention has focused on the metabolic and behavi...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Maillard, J., Park, S., Croizier, S., Vanacker, C., Cook, J. H., Prevot, V., Tauber, M., Bouret, S. G. Tags: ARTICLES Source Type: research

Differential molecular and behavioural alterations in mouse models of GABRG2 haploinsufficiency versus dominant negative mutations associated with human epilepsy
Genetic epilepsy is a common disorder with phenotypic variation, but the basis for the variation is unknown. Comparing the molecular pathophysiology of mutations in the same epilepsy gene may provide mechanistic insights into the phenotypic heterogeneity. GABRG2 is an established epilepsy gene, and mutations in it produce epilepsy syndromes with varying severities. The disease phenotype in some cases may be caused by simple loss of subunit function (functional haploinsufficiency), while others may be caused by loss-of-function plus dominant negative suppression and other cellular toxicity. Detailed molecular defects and th...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Warner, T. A., Shen, W., Huang, X., Liu, Z., Macdonald, R. L., Kang, J.-Q. Tags: ARTICLES Source Type: research

Sustained AMPK activation improves muscle function in a mitochondrial myopathy mouse model by promoting muscle fiber regeneration
Acute pharmacological activation of adenosine monophosphate (AMP)-kinase using 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside (AICAR) has been shown to improve muscle mitochondrial function by increasing mitochondrial biogenesis. We asked whether prolonged AICAR treatment is beneficial in a mouse model of slowly progressing mitochondrial myopathy (Cox10-Mef2c-Cre), and whether the compensatory mechanism is indeed an increase in mitochondrial biogenesis. We treated the animals for 3 months and found that sustained AMP-dependent kinase activation improved cytochrome c oxidase activity, rescued the motor phenotype and de...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Peralta, S., Garcia, S., Yin, H. Y., Arguello, T., Diaz, F., Moraes, C. T. Tags: ARTICLES Source Type: research

A Drosophila model of Huntington disease-like 2 exhibits nuclear toxicity and distinct pathogenic mechanisms from Huntington disease
Huntington disease-like 2 (HDL2) and Huntington disease (HD) are adult-onset neurodegenerative diseases characterized by movement disorders, psychiatric disturbances and cognitive decline. Brain tissue from HD and HDL2 patients shows degeneration of the striatum and ubiquitinated inclusions immunoreactive for polyglutamine (polyQ) antibodies. Despite these similarities, the diseases result from different genetic mutations. HD is caused by a CAG repeat expansion in the huntingtin (HTT) gene, while HDL2 results from an expansion at the junctophilin 3 (JPH3) locus. Recent evidence indicates that the HDL2 expansion may give ri...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Krench, M., Cho, R. W., Littleton, J. T. Tags: ARTICLES Source Type: research

iPSC-derived LewisX+CXCR4+{beta}1-integrin+ neural stem cells improve the amyotrophic lateral sclerosis phenotype by preserving motor neurons and muscle innervation in human and rodent models
Amyotrophic lateral sclerosis (ALS) is a fatal incurable neurodegenerative disease characterized by progressive degeneration of motor neurons (MNs), leading to relentless muscle paralysis. In the early stage of the disease, MN loss and consequent muscle denervation are compensated by axonal sprouting and reinnervation by the remaining MNs, but this mechanism is insufficient in the long term. Here, we demonstrate that induced pluripotent stem cell-derived neural stem cells (NSCs), in particular the subpopulation positive for LewisX-CXCR4-β1-integrin, enhance neuronal survival and axonal growth of human ALS-derived MNs ...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Nizzardo, M., Bucchia, M., Ramirez, A., Trombetta, E., Bresolin, N., Comi, G. P., Corti, S. Tags: ARTICLES Source Type: research

The unconventional secretion of ARMS2
In conclusion, in this work we show that ARMS2 is externalized via an unconventional pathway bypassing Golgi. Its intracellular separation from the classical secretion pathway suggests that the maturation of the protein requires a specific biochemical niche and/or may be needed to impede the premature formation of unwanted protein-protein interactions. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Kortvely, E., Hauck, S. M., Behler, J., Ho, N., Ueffing, M. Tags: ARTICLES Source Type: research

Table of Contents
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Tags: ARTICLES Source Type: research

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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Tags: ARTICLES Source Type: research

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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Tags: ARTICLES Source Type: research

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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Tags: ARTICLES Source Type: research

An extended genome-wide association study identifies novel susceptibility loci for nasopharyngeal carcinoma
To further identify novel susceptibility loci of nasopharyngeal carcinoma (NPC), we here extended our previous genome-wide association study (GWAS) by boosting statistical power with larger sample size and validating more SNPs in the ranking list based on the GWAS P-values. The discovery stage consisting of 463,250 SNPs in 1,583 cases and 2,979 controls of southern Chinese ancestry revealed 1,257 top SNPs to be associated with NPC, which were brought forward for validation in 1,925 cases and 1,947 controls of southern Chinese. Further, 11 SNPs were selected for another independent validation in 3,538 cases and 3,644 contro...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Cui, Q., Feng, Q.-S., Mo, H.-Y., Sun, J., Xia, Y.-F., Zhang, H., Foo, J. N., Guo, Y.-M., Chen, L.-Z., Li, M., Liu, W.-S., Xu, M., Zhou, G., He, F., Yu, X., Jia, W.-H., Liu, J., Zeng, Y.-X., Bei, J.-X. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research

Biochemical evidence for a mitochondrial genetic modifier in the phenotypic manifestation of Lebers hereditary optic neuropathy-associated mitochondrial DNA mutation
In this study, we demonstrated that the LHON susceptibility allele (m.14502T> C, p. 58I> V) in the ND6 gene modulated the phenotypic expression of primary LHON-associated m.11778G> A mutation. Twenty-two Han Chinese pedigrees carrying m.14502T> C and m.11778G> A mutations exhibited significantly higher penetrance of optic neuropathy than those carrying only m.11778G> A mutation. We performed functional assays using the cybrid cell models, generated by fusing mtDNA-less o cells with enucleated cells from LHON patients carrying both m.11778G> A and m.14502T> C mutations, only m.14502T> C or m.11778...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Jiang, P., Liang, M., Zhang, C., Zhao, X., He, Q., Cui, L., Liu, X., Sun, Y.-H., Fu, Q., Ji, Y., Bai, Y., Huang, T., Guan, M.-X. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research

Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells
Niemann-Pick type C disease (NP-C) is a progressive lysosomal lipid storage disease caused by mutations in the NPC1 and NPC2 genes. NPC1 is essential for transporting cholesterol and other lipids out of lysosomes, but little is known about the mechanisms that control its cellular abundance and localization. Here we show that a reduction of TMEM97, a cholesterol-responsive NPC1-binding protein, increases NPC1 levels in cells through a post-transcriptional mechanism. Reducing TMEM97 through RNA-interference reduces lysosomal lipid storage and restores cholesterol trafficking to the endoplasmic reticulum in cell models of NP-...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Ebrahimi-Fakhari, D., Wahlster, L., Bartz, F., Werenbeck-Ueding, J., Praggastis, M., Zhang, J., Joggerst-Thomalla, B., Theiss, S., Grimm, D., Ory, D. S., Runz, H. Tags: ARTICLES Source Type: research

Deletion of amelotin exons 3-6 is associated with amelogenesis imperfecta
This study demonstrates for the first time that AMTN mutations cause non-syndromic human AI and explores the human phenotype, comparing it with that of mice with disrupted Amtn function. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Smith, C. E. L., Murillo, G., Brookes, S. J., Poulter, J. A., Silva, S., Kirkham, J., Inglehearn, C. F., Mighell, A. J. Tags: ARTICLES Source Type: research

Ectodysplasin signalling deficiency in mouse models of hypohidrotic ectodermal dysplasia leads to middle ear and nasal pathology
We report that otitis media, rhinitis and nasopharyngitis occur at high frequency in Eda and Edar mutant mice and explore the pathogenic mechanisms related to glandular function, microbial and immune parameters in these lines. Nasopharynx auditory tube glands fail to develop in HED mutant mice and the functional implications include loss of lysozyme secretion, reduced mucociliary clearance and overgrowth of nasal commensal bacteria accompanied by neutrophil exudation. Heavy nasopharynx foreign body load and loss of gland protection alters the auditory tube gating function and the auditory tubes can become pathologically di...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Azar, A., Piccinelli, C., Brown, H., Headon, D., Cheeseman, M. Tags: ARTICLES Source Type: research

Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles
In preclinical models for Duchenne muscular dystrophy, dystrophin restoration during adeno-associated virus (AAV)-U7-mediated exon-skipping therapy was shown to decrease drastically after six months in treated muscles. This decline in efficacy is strongly correlated with the loss of the therapeutic AAV genomes, probably due to alterations of the dystrophic myofiber membranes. To improve the membrane integrity of the dystrophic myofibers at the time of AAV-U7 injection, mdx muscles were pre-treated with a single dose of the peptide-phosphorodiamidate morpholino (PPMO) antisense oligonucleotides that induced temporary dystro...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Peccate, C., Mollard, A., Le Hir, M., Julien, L., McClorey, G., Jarmin, S., Le Heron, A., Dickson, G., Benkhelifa-Ziyyat, S., Pietri-Rouxel, F., Wood, M. J., Voit, T., Lorain, S. Tags: ARTICLES Source Type: research

Rescue of neural crest-derived phenotypes in a zebrafish CHARGE model by Sox10 downregulation
We report for the first time, defects in myelinating Schwann cells, enteric neurons and pigment cells in a CHARGE model. We also observe defects in the specification of peripheral neurons and the craniofacial skeleton as previously reported. Chd7 morphants have impaired migration of neural crest cells and deregulation of sox10 expression from the early stages. Knocking down Sox10 in the zebrafish CHARGE model rescued the defects in Schwann cells and craniofacial cartilage. Our zebrafish CHARGE model thus reveals important regulatory roles for Chd7 at multiple points of neural crest development viz., migration, fate choice ...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Asad, Z., Pandey, A., Babu, A., Sun, Y., Shevade, K., Kapoor, S., Ullah, I., Ranjan, S., Scaria, V., Bajpai, R., Sachidanandan, C. Tags: ARTICLES Source Type: research

Cancer-associated isocitrate dehydrogenase mutations induce mitochondrial DNA instability
A major advance in understanding the progression and prognostic outcome of certain cancers, such as low-grade gliomas, acute myeloid leukaemia, and chondrosarcomas, has been the identification of early-occurring mutations in the NADP+-dependent isocitrate dehydrogenase genes IDH1 and IDH2. These mutations result in the production of the onco-metabolite D-2-hydroxyglutarate (2HG), thought to contribute to disease progression. To better understand the mechanisms of 2HG pathophysiology, we introduced the analogous glioma-associated mutations into the NADP+ isocitrate dehydrogenase genes (IDP1, IDP2, IDP3) in Saccharomyces cer...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Kingsbury, J. M., Shamaprasad, N., Billmyre, R. B., Heitman, J., Cardenas, M. E. Tags: ARTICLES Source Type: research

LRRK2 modulates microglial activity through regulation of chemokine (C-X3-C) receptor 1 -mediated signalling pathways
In conclusion, our findings reveal a previously unknown regulatory role for LRRK2 in CX3CR1 signalling and suggest that an increase of CX3CR1 activity contributes to the attenuated inflammatory responses in Lrrk2-null microglia. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Ma, B., Xu, L., Pan, X., Sun, L., Ding, J., Xie, C., Koliatsos, V. E., Cai, H. Tags: ARTICLES Source Type: research

The K153Del PRPH2 mutation differentially impacts photoreceptor structure and function
Peripherin 2 (Prph2) is a photoreceptor tetraspanin, and deletion of codon 153 (K153) leads to retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in the same family. To study this variability, we generated a K153-Prph2 knockin mouse. K153-Prph2 cannot form the complexes required for outer segment formation, and in cones cannot interact with its binding partner rod outer segment membrane protein 1. K153 causes dominant defects in rod and cone function; however, rod but not cone ultrastructure is improved by the presence of K153-Prph2. Likewise, supplementation of K153 heterozygotes with WT-Prph2 results in s...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Chakraborty, D., Conley, S. M., Zulliger, R., Naash, M. I. Tags: ARTICLES Source Type: research