Subscriptions Page
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Editorial Board
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Front Cover
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - November 27, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation
Cohort-wide very low-depth whole-genome sequencing (WGS) can comprehensively capture low-frequency sequence variation for the cost of a dense genome-wide genotyping array. Here, we analyse 1x sequence data across the APOC3 gene in a founder population from the island of Crete in Greece (n = 1239) and find significant evidence for association with blood triglyceride levels with the previously reported R19X cardioprotective null mutation (β = –1.09, = 0.163, P = 8.2 x 10–11) and a second loss of function mutation, rs138326449 (β = –1.17, = 0.188, P = 1.14 x 10–9). The signal cannot be recapi...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Gilly, A., Ritchie, G. R., Southam, L., Farmaki, A.-E., Tsafantakis, E., Dedoussis, G., Zeggini, E. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Genome wide association study identifies two loci associated with cadmium in erythrocytes among never-smokers
Conclusion: This genome-wide study of never smokers from the general population identified two independent regions related to erythrocyte cadmium. The strongest locus covers the XKR9 and LACTB2 genes, which both could have related functions in cadmium absorption and metabolism. Replication studies are needed to confirm the findings and mechanisms should be further investigated. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Borne, Y., Söderholm, M., Barregard, L., Fagerberg, B., Persson, M., Melander, O., Thevenod, F., Hedblad, B., Engström, G. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Shorter telomere length in Europeans than in Africans due to polygenetic adaptation
Leukocyte telomere length (LTL), which reflects telomere length in other somatic tissues, is a complex genetic trait. Eleven SNPs have been shown in genome-wide association studies to be associated with LTL at a genome-wide level of significance within cohorts of European ancestry. It has been observed that LTL is longer in African Americans than in Europeans. The underlying reason for this difference is unknown. Here we show that LTL is significantly longer in sub-Saharan Africans than in both Europeans and African Americans. Based on the 11 LTL-associated alleles and genetic data in phase 3 of the 1000 Genomes Project, w...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Hansen, M. E. B., Hunt, S. C., Stone, R. C., Horvath, K., Herbig, U., Ranciaro, A., Hirbo, J., Beggs, W., Reiner, A. P., Wilson, J. G., Kimura, M., De Vivo, I., Chen, M. M., Kark, J. D., Levy, D., Nyambo, T., Tishkoff, S. A., Aviv, A. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Fasudil treatment in adult reverses behavioural changes and brain ventricular enlargement in Oligophrenin-1 mouse model of intellectual disability
Loss of function mutations in human Oligophrenin1 (OPHN1) gene are responsible for syndromic intellectual disability (ID) associated with cerebellar hypoplasia and cerebral ventricles enlargement. Functional studies in rodent models suggest that OPHN1 linked ID is a consequence of abnormal synaptic transmission and shares common pathophysiological mechanisms with other cognitive disorders. Variants of this gene have been also identified in autism spectrum disorder and schizophrenia. The advanced understanding of the mechanisms underlying OPHN1-related ID, allowed us to develop a therapeutic approach targeting the Ras homol...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Meziane, H., Khelfaoui, M., Morello, N., Hiba, B., Calcagno, E., Reibel-Foisset, S., Selloum, M., Chelly, J., Humeau, Y., Riet, F., Zanni, G., Herault, Y., Bienvenu, T., Giustetto, M., Billuart, P. Tags: ARTICLES Source Type: research
Inpp5e suppresses polycystic kidney disease via inhibition of PI3K/Akt-dependent mTORC1 signaling
Polycystic kidney disease (PKD) is a common cause of renal failure with few effective treatments. INPP5E is an inositol polyphosphate 5-phosphatase that dephosphorylates phosphoinositide 3-kinase (PI3K)-generated PI(3,4,5)P3 and is mutated in ciliopathy syndromes. Germline Inpp5e deletion is embryonically lethal, attributed to cilia stability defects, and is associated with polycystic kidneys. However, the molecular mechanisms responsible for PKD development upon Inpp5e loss remain unknown. Here, we show conditional inactivation of Inpp5e in mouse kidney epithelium results in severe PKD and renal failure, associated with a...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Hakim, S., Dyson, J. M., Feeney, S. J., Davies, E. M., Sriratana, A., Koenig, M. N., Plotnikova, O. V., Smyth, I. M., Ricardo, S. D., Hobbs, R. M., Mitchell, C. A. Tags: ARTICLES Source Type: research
Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21)
Bardet Biedl syndrome (BBS) is a multisystem genetically heterogeneous ciliopathy that most commonly leads to obesity, photoreceptor degeneration, digit anomalies, genito-urinary abnormalities, as well as cognitive impairment with autism, among other features. Sequencing of a DNA sample from a 17-year-old female affected with BBS did not identify any mutation in the known BBS genes. Whole-genome sequencing identified a novel loss-of-function disease-causing homozygous mutation (K102*) in C8ORF37, a gene coding for a cilia protein. The proband was overweight (body mass index 29.1) with a slowly progressive rod-cone dystroph...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Heon, E., Kim, G., Qin, S., Garrison, J. E., Tavares, E., Vincent, A., Nuangchamnong, N., Scott, C. A., Slusarski, D. C., Sheffield, V. C. Tags: ARTICLES Source Type: research
Enhanced mitochondrial biogenesis ameliorates disease phenotype in a full-length mouse model of Huntingtons disease
Huntington’s disease (HD) is a devastating illness and at present there is no disease modifying therapy or cure for it; and management of the disease is limited to a few treatment options for amelioration of symptoms. Recently, we showed that the administration of bezafibrate, a pan-PPAR agonist, increases the expression of PGC-1α and mitochondrial biogenesis, and improves phenotype and survival in R6/2 transgenic mouse model of HD. Since the R6/2 mice represent a ‘truncated’ huntingtin (Htt) mouse model of HD, we tested the efficacy of bezafibrate in a ‘full-length’ Htt mouse model, the...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Chandra, A., Sharma, A., Calingasan, N. Y., White, J. M., Shurubor, Y., Yang, X. W., Beal, M. F., Johri, A. Tags: ARTICLES Source Type: research
Reduction of ciliary length through pharmacologic or genetic inhibition of CDK5 attenuates polycystic kidney disease in a model of nephronophthisis
Polycystic kidney diseases (PKDs) comprise a subgroup of ciliopathies characterized by the formation of fluid-filled kidney cysts and progression to end-stage renal disease. A mechanistic understanding of cystogenesis is crucial for the development of viable therapeutic options. Here, we identify CDK5, a kinase active in post mitotic cells, as a new and important mediator of PKD progression. We show that long-lasting attenuation of PKD in the juvenile cystic kidneys (jck) mouse model of nephronophthisis by pharmacological inhibition of CDK5 using either R-roscovitine or S-CR8 is accompanied by sustained shortening of cilia...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Husson, H., Moreno, S., Smith, L. A., Smith, M. M., Russo, R. J., Pitstick, R., Sergeev, M., Ledbetter, S. R., Bukanov, N. O., Lane, M., Zhang, K., Billot, K., Carlson, G., Shah, J., Meijer, L., Beier, D. R., Ibraghimov-Beskrovnaya, O. Tags: ARTICLES Source Type: research
Molecular basis of classic galactosemia from the structure of human galactose 1-phosphate uridylyltransferase
Classic galactosemia is a potentially lethal disease caused by the dysfunction of galactose 1-phosphate uridylyltransferase (GALT). Over 300 disease-associated GALT mutations have been reported, with the majority being missense changes, although a better understanding of their underlying molecular effects has been hindered by the lack of structural information for the human enzyme. Here, we present the 1.9 Å resolution crystal structure of human GALT (hGALT) ternary complex, revealing a homodimer arrangement that contains a covalent uridylylated intermediate and glucose-1-phosphate in the active site, as well as a st...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: McCorvie, T. J., Kopec, J., Pey, A. L., Fitzpatrick, F., Patel, D., Chalk, R., Shrestha, L., Yue, W. W. Tags: ARTICLES Source Type: research
ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene
Cardiomyopathy caused by lamin A/C gene mutations (LMNA cardiomyopathy) is characterized by increased myocardial fibrosis, which impairs left ventricular relaxation and predisposes to heart failure, and cardiac conduction abnormalities. While we previously discovered abnormally elevated extracellular signal-regulated kinase 1/2 (ERK1/2) activities in heart in LMNA cardiomyopathy, its role on the development of myocardial fibrosis remains unclear. We now showed that transforming growth factor (TGF)-β/Smad signaling participates in the activation of ERK1/2 signaling in LMNA cardiomyopathy. ERK1/2 acts on connective tiss...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Chatzifrangkeskou, M., Le Dour, C., Wu, W., Morrow, J. P., Joseph, L. C., Beuvin, M., Sera, F., Homma, S., Vignier, N., Mougenot, N., Bonne, G., Lipson, K. E., Worman, H. J., Muchir, A. Tags: ARTICLES Source Type: research
5-Hydroxymethylcytosine-mediated alteration of transposon activity associated with the exposure to adverse in utero environments in human
Preeclampsia and gestational diabetes mellitus (GDM) are the most common clinical conditions in pregnancy that could result in adverse in utero environments. Fetal exposure to poor environments may raise the long-term risk of postnatal disorders, while epigenetic modifications could be involved. Recent research has implicated involvement of 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine, via oxidation by ten–eleven translocation (TET) enzymes, in DNA methylation-related plasticity. Here, we show that the TET2 expression and 5hmC abundance are significantly altered in the umbilical veins of G...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Sun, M., Song, M. M., Wei, B., Gao, Q., Li, L., Yao, B., Chen, L., Lin, L., Dai, Q., Zhou, X., Tao, J., Chen, J., He, C., Jin, P., Xu, Z. Tags: ARTICLES Source Type: research
Failure to up-regulate transcription of genes necessary for muscle adaptation underlies limb girdle muscular dystrophy 2A (calpainopathy)
Limb girdle muscular dystrophy 2A is due to loss-of-function mutations in the Calpain 3 (CAPN3) gene. Our previous data suggest that CAPN3 helps to maintain the integrity of the triad complex in skeletal muscle. In Capn3 knock-out mice (C3KO), Ca2+ release and Ca2+/calmodulin kinase II (CaMKII) signaling are attenuated. We hypothesized that calpainopathy may result from a failure to transmit loading-induced Ca2+-mediated signals, necessary to up-regulate expression of muscle adaptation genes. To test this hypothesis, we compared transcriptomes of muscles from wild type (WT) and C3KO mice subjected to endurance exercise. In...
Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Kramerova, I., Ermolova, N., Eskin, A., Hevener, A., Quehenberger, O., Armando, A. M., Haller, R., Romain, N., Nelson, S. F., Spencer, M. J. Tags: ARTICLES Source Type: research
