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 ...
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 containin...
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
