Loss of human disease protein retinitis pigmentosa GTPase regulator (RPGR) differentially affects rod or cone-enriched retina
It is unclear how genes, such as RPGR (retinitis pigmentosa guanine triphosphatase regulator) that are expressed in both rods and cones, cause variable disease pathogenesis. Using transcriptomic analysis, we show that loss of RPGR in a rod-dominant mouse retina (Rpgrko) results in predominant alterations in genes involved in actin cytoskeletal dynamics, prior to onset of degeneration. We validated these findings and found an increase in activated RhoA-GTP levels and polymerized F-actin in the Rpgrko mouse retina. To assess the effect of the loss of RPGR in the all-cone region of the human retina, we used Nrl–/–...
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Rao, K. N., Li, L., Zhang, W., Brush, R. S., Rajala, R. V. S., Khanna, H. Tags: ARTICLES Source Type: research
The ubiquitin ligase Ubr4 controls stability of podocin/MEC-2 supercomplexes
The PHB-domain protein podocin maintains the renal filtration barrier and its mutation is an important cause of hereditary nephrotic syndrome. Podocin and its Caenorhabditis elegans orthologue MEC-2 have emerged as key components of mechanosensitive membrane protein signalling complexes. Whereas podocin resides at a specialized cell junction at the podocyte slit diaphragm, MEC-2 is found in neurons required for touch sensitivity. Here, we show that the ubiquitin ligase Ubr4 is a key component of the podocin interactome purified both from cultured podocytes and native glomeruli. It colocalizes with podocin and regulates its...
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Rinschen, M. M., Bharill, P., Wu, X., Kohli, P., Reinert, M. J., Kretz, O., Saez, I., Schermer, B., Höhne, M., Bartram, M. P., Aravamudhan, S., Brooks, B. R., Vilchez, D., Huber, T. B., Müller, R.-U., Krüger, M., Benzing, T. Tags: ARTICLES Source Type: research
Glucose metabolism during fasting is altered in experimental porphobilinogen deaminase deficiency
In conclusion, AIP mice showed a different response to fasting as measured by altered carbohydrate metabolism in the liver and modified glucose consumption in the brain cortex. Glucose homeostasis in fasted AIP mice was efficiently normalized after restoration of PBGD gene expression in the liver. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Collantes, M., Serrano-Mendioroz, I., Benito, M., Molinet-Dronda, F., Delgado, M., Vinaixa, M., Sampedro, A., Enriquez de Salamanca, R., Prieto, E., Pozo, M. A., Penuelas, I., Corrales, F. J., Barajas, M., Fontanellas, A. Tags: ARTICLES Source Type: research
Phosphatidylserine enhances IKBKAP transcription by activating the MAPK/ERK signaling pathway
In conclusion, our results demonstrate that PS activates the MAPK/ERK signaling pathway, resulting in activation of transcription factors that bind the promoter region of IKBKAP and thus enhancing its transcription. Therefore, compounds that activate the MAPK/ERK signaling pathway could constitute potential treatments for FD. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Donyo, M., Hollander, D., Abramovitch, Z., Naftelberg, S., Ast, G. Tags: ARTICLES Source Type: research
Haploinsufficiency of BAZ1B contributes to Williams syndrome through transcriptional dysregulation of neurodevelopmental pathways
Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ~28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of WS. In patient-derived stem cells and neurons, we determined the expression profile of the Williams–Beuren syndrome critical region-deleted genes and the genome-wide transcriptional consequences ...
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Lalli, M. A., Jang, J., Park, J.-H. C., Wang, Y., Guzman, E., Zhou, H., Audouard, M., Bridges, D., Tovar, K. R., Papuc, S. M., Tutulan-Cunita, A. C., Huang, Y., Budisteanu, M., Arghir, A., Kosik, K. S. Tags: ARTICLES Source Type: research
Genetic deletion of keratin 8 corrects the altered bone formation and osteopenia in a mouse model of cystic fibrosis
Patients with cystic fibrosis (CF) display low bone mass and alterations in bone formation. Mice carrying the F508del genetic mutation in the cystic fibrosis conductance regulator (Cftr) gene display reduced bone formation and decreased bone mass. However, the underlying molecular mechanisms leading to these skeletal defects are unknown, which precludes the development of an efficient anti-osteoporotic therapeutic strategy. Here we report a key role for the intermediate filament protein keratin 8 (Krt8), in the osteoblast dysfunctions in F508del-Cftr mice. We found that murine and human osteoblasts express Cftr and Krt8 at...
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Le Henaff, C., Faria Da Cunha, M., Hatton, A., Tondelier, D., Marty, C., Collet, C., Zarka, M., Geoffroy, V., Zatloukal, K., Laplantine, E., Edelman, A., Sermet-Gaudelus, I., Marie, P. J. Tags: ARTICLES Source Type: research
Cockayne syndrome-derived neurons display reduced synapse density and altered neural network synchrony
Cockayne syndrome (CS) is a rare genetic disorder in which 80% of cases are caused by mutations in the Excision Repair Cross-Complementation group 6 gene (ERCC6). The encoded ERCC6 protein is more commonly referred to as Cockayne Syndrome B protein (CSB). Classical symptoms of CS patients include failure to thrive and a severe neuropathology characterized by microcephaly, hypomyelination, calcification and neuronal loss. Modeling the neurological aspect of this disease has proven difficult since murine models fail to mirror classical neurological symptoms. Therefore, a robust human in vitro cellular model would advance our...
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Vessoni, A. T., Herai, R. H., Karpiak, J. V., Leal, A. M. S., Trujillo, C. A., Quinet, A., Agnez Lima, L. F., Menck, C. F. M., Muotri, A. R. Tags: ARTICLES Source Type: research
Actin capping protein CAPZB regulates cell morphology, differentiation, and neural crest migration in craniofacial morphogenesis
CAPZB is an actin-capping protein that caps the growing end of F-actin and modulates the cytoskeleton and tethers actin filaments to the Z-line of the sarcomere in muscles. Whole-genome sequencing was performed on a subject with micrognathia, cleft palate and hypotonia that harbored a de novo, balanced chromosomal translocation that disrupts the CAPZB gene. The function of capzb was analyzed in the zebrafish model. capzb–/– mutants exhibit both craniofacial and muscle defects that recapitulate the phenotypes observed in the human subject. Loss of capzb affects cell morphology, differentiation and neural crest m...
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Authors: Mukherjee, K., Ishii, K., Pillalamarri, V., Kammin, T., Atkin, J. F., Hickey, S. E., Xi, Q. J., Zepeda, C. J., Gusella, J. F., Talkowski, M. E., Morton, C. C., Maas, R. L., Liao, E. C. Tags: ARTICLES Source Type: research
Contents Page
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
Subscription Page
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
Editorial Board
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - March 11, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes
Over 100 associated genetic loci have been robustly associated with schizophrenia. Gene prioritization and pathway analysis have focused on a priori hypotheses and thus may have been unduly influenced by prior assumptions and missed important causal genes and pathways. Using a data-driven approach, we show that genes in associated loci: (1) are highly expressed in cortical brain areas; (2) are enriched for ion channel pathways (false discovery rates <0.05); and (3) contain 62 genes that are functionally related to each other and hence represent promising candidates for experimental follow up. We validate the relevance o...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Pers, T. H., Timshel, P., Ripke, S., Lent, S., Schizophrenia Working Group of the Psychiatric Genomics Consortium, Sullivan, P. F., O'Donovan, M. C., Franke, L., Hirschhorn, J. N. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Exploring the complete mutational space of the LDL receptor LA5 domain using molecular dynamics: linking SNPs with disease phenotypes in familial hypercholesterolemia
Familial hypercholesterolemia (FH), a genetic disorder with a prevalence of 0.2%, represents a high-risk factor to develop cardiovascular and cerebrovascular diseases. The majority and most severe FH cases are associated to mutations in the receptor for low-density lipoproteins receptor (LDL-r), but the molecular basis explaining the connection between mutation and phenotype is often unknown, which hinders early diagnosis and treatment of the disease. We have used atomistic simulations to explore the complete SNP mutational space (227 mutants) of the LA5 repeat, the key domain for interacting with LDL that is coded in the ...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Angarica, V. E., Orozco, M., Sancho, J. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Fine mapping the MHC region identified four independent variants modifying susceptibility to chronic hepatitis B in Han Chinese
Several genome-wide association studies (GWAS) have demonstrated the association between genetic variants in the major histocompatibility complex (MHC) region and chronic hepatitis B (CHB) virus infection, but it is still unknown about the disease-causing loci and potential mechanisms owing to the complicated linkage disequilibrium for this region. To systematically characterize the MHC variations in relation to the CHB infection, we fine mapped the MHC region on our existing GWAS data with SNP2HLA taken the Pan-Asian panel as reference and finally identified four independent associations. The HLA-DPβ1 amino acid posi...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Zhu, M., Dai, J., Wang, C., Wang, Y., Qin, N., Ma, H., Song, C., Zhai, X., Yang, Y., Liu, J., Liu, L., Li, S., Liu, J., Yang, H., Zhu, F., Shi, Y., Shen, H., Jin, G., Zhou, W., Hu, Z. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
