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Human Genetics

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https://www.readbyqxmd.com/read/28664341/the-activity-of-the-serotonin-receptor-2c-is-regulated-by-alternative-splicing
#1
REVIEW
Stefan Stamm, Samuel B Gruber, Alexander G Rabchevsky, Ronald B Emeson
The central nervous system-specific serotonin receptor 2C (5HT2C) controls key physiological functions, such as food intake, anxiety, and motoneuron activity. Its deregulation is involved in depression, suicidal behavior, and spasticity, making it the target for antipsychotic drugs, appetite controlling substances, and possibly anti-spasm agents. Through alternative pre-mRNA splicing and RNA editing, the 5HT2C gene generates at least 33 mRNA isoforms encoding 25 proteins. The 5HT2C is a G-protein coupled receptor that signals through phospholipase C, influencing the expression of immediate/early genes like c-fos...
June 29, 2017: Human Genetics
https://www.readbyqxmd.com/read/28608251/rna-processing-as-an-alternative-route-to-attack-glioblastoma
#2
REVIEW
Fabiana Marcelino Meliso, Christopher G Hubert, Pedro A Favoretto Galante, Luiz O Penalva
Genomic analyses have become an important tool to identify new avenues for therapy. This is especially true for cancer types with extremely poor outcomes, since our lack of effective therapies offers no tangible clinical starting point to build upon. The highly malignant brain tumor glioblastoma (GBM) exemplifies such a refractory cancer, with only 15 month average patient survival. Analyses of several hundred GBM samples compiled by the TCGA (The Cancer Genome Atlas) have produced an extensive transcriptomic map, identified prevalent chromosomal alterations, and defined important driver mutations...
June 12, 2017: Human Genetics
https://www.readbyqxmd.com/read/28597072/normal-and-altered-pre-mrna-processing-in-the-dmd-gene
#3
REVIEW
Sylvie Tuffery-Giraud, Julie Miro, Michel Koenig, Mireille Claustres
Splicing of pre-mRNA is a crucial regulatory stage in the pathway of gene expression controlled by multiple post- and co-transcriptional mechanisms. The large Duchenne muscular dystrophy gene encoding the protein dystrophin provides a striking example of the complexity of human pre-mRNAs. In this review, we summarize the current state of knowledge about canonical and non-canonical splicing in the DMD pre-mRNA, with a focus on mechanisms that take place in the full-length transcript isoform expressed in human skeletal muscle...
June 9, 2017: Human Genetics
https://www.readbyqxmd.com/read/28567521/comprehensive-evaluation-of-disease-and-trait-specific-enrichment-for-eight-functional-elements-among-gwas-identified-variants
#4
Christina A Markunas, Eric O Johnson, Dana B Hancock
Genome-wide association study (GWAS)-identified variants are enriched for functional elements. However, we have limited knowledge of how functional enrichment may differ by disease/trait and tissue type. We tested a broad set of eight functional elements for enrichment among GWAS-identified SNPs (p < 5×10(-8)) from the NHGRI-EBI Catalog across seven disease/trait categories: cancer, cardiovascular disease, diabetes, autoimmune disease, psychiatric disease, neurological disease, and anthropometric traits...
May 31, 2017: Human Genetics
https://www.readbyqxmd.com/read/28540413/a-recessive-mutation-in-beta-iv-spectrin-sptbn4-associates-with-congenital-myopathy-neuropathy-and-central-deafness
#5
Ellen Knierim, Esther Gill, Franziska Seifert, Susanne Morales-Gonzalez, Sathya D Unudurthi, Thomas J Hund, Werner Stenzel, Markus Schuelke
Congenital myopathies are a heterogeneous group of muscle disorders that are often genetically determined. Here, we investigated a boy with congenital myopathy, deafness, and neuropathy from a consanguineous Kurdish family by autozygosity mapping and whole exome sequencing. We found a homozygous nonsense mutation in SPTBN4 [c.1597C>T, NM_020971.2; p.(Q533*), NP_066022.2; ClinVar SUB2292235] encoding βIV-spectrin, a non-erythrocytic member of the β-spectrin family. Western blot confirmed the absence of the full-length 288 kDa isoform in muscle and of a specific 72 kDa isoform in fibroblasts...
May 24, 2017: Human Genetics
https://www.readbyqxmd.com/read/28540412/a-distal-auxiliary-element-facilitates-cleavage-and-polyadenylation-of-dux4-mrna-in-the-pathogenic-haplotype-of-fshd
#6
Natoya Peart, Eric J Wagner
The degenerative muscle disorder facioscapulohumeral dystrophy (FSHD) is thought to be caused by the inappropriate expression of the Double Homeobox 4 (Dux4) protein in muscle cells leading to apoptosis. Expression of Dux4 in the major form of FSHD is a function of two contributing molecular changes: contractions in the D4Z4 microsatellite repeat region where Dux4 is located and an SNP present within a region downstream of the D4Z4. This SNP provides a functional, yet non-consensus polyadenylation signal (PAS) is used for the Dux4 mRNA 3' end processing...
May 24, 2017: Human Genetics
https://www.readbyqxmd.com/read/28528403/assessing-the-causal-relationship-between-obesity-and-venous-thromboembolism-through-a-mendelian-randomization-study
#7
Sara Lindström, Marine Germain, Marta Crous-Bou, Erin N Smith, Pierre-Emmanuel Morange, Astrid van Hylckama Vlieg, Hugoline G de Haan, Daniel Chasman, Paul Ridker, Jennifer Brody, Mariza de Andrade, John A Heit, Weihong Tang, Immaculata DeVivo, Francine Grodstein, Nicholas L Smith, David Tregouet, Christopher Kabrhel
Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry...
May 20, 2017: Human Genetics
https://www.readbyqxmd.com/read/28526948/an-innovative-strategy-to-clone-positive-modifier-genes-of-defects-caused-by-mtdna-mutations-mrps18c-as-suppressor-gene-of-m-3946g-a-mutation-in-mt-nd1-gene
#8
María Elena Rodríguez-García, Francisco Javier Cotrina-Vinagre, Patricia Carnicero-Rodríguez, Francisco Martínez-Azorín
We have developed a new functional complementation approach to clone modifier genes which overexpression is able to suppress the biochemical defects caused by mtDNA mutations (suppressor genes). This strategy consists in transferring human genes into respiratory chain-deficient fibroblasts, followed by a metabolic selection in a highly selective medium. We used a normalized expression cDNA library in an episomal vector (pREP4) to transfect the fibroblasts, and a medium with glutamine and devoid of any carbohydrate source to select metabolically...
May 19, 2017: Human Genetics
https://www.readbyqxmd.com/read/28508290/crispr-cas9-mediated-somatic-and-germline-gene-correction-to-restore-hemostasis-in-hemophilia-b-mice
#9
Cong Huai, Chenqiang Jia, Ruilin Sun, Peipei Xu, Taishan Min, Qihan Wang, Chengde Zheng, Hongyan Chen, Daru Lu
Hemophilia B (HB) is an X-linked disorder caused by defects of F9 encoded coagulation factor IX, which is an ideal model for gene therapy. Most existing HB gene therapies are based on viral mediated gene supplementation, which could increase immunoreaction. In this study, CRISPR/Cas9 system was used for gene correction in an F9 mutant HB mouse model in both adult mice (in vivo) and in germline cells (ex vivo). In vivo, naked Cas9-sgRNA plasmid and donor DNA were delivered to HB mice livers to recover the mutation via hydrodynamic tail vein (HTV) injection...
May 15, 2017: Human Genetics
https://www.readbyqxmd.com/read/28508289/somatic-mosaicism-with-reversion-to-normality-of-a-mutated-transthyretin-allele-related-to-a-familial-amyloidotic-polyneuropathy
#10
Concetta Federico, Ketty Dugo, Francesca Bruno, Anna Maria Longo, Agata Grillo, Salvatore Saccone
Familial amyloidotic polyneuropathy (FAP) is a progressive neuropathy, with onset in adulthood and high mortality. It is related to an altered transthyretin (TTR) plasma protein, mainly produced by the liver and responsible for amyloid deposit in the peripheral nervous system. SNPs in the TTR gene were associated with FAP, and the G>C substitution (NM_000371.3:c.325G>C) in the 109th codon (GAG vs CAG; NP_362.1:p.E109Q) was previously described in Sicily (Italy). Here, we report on a Sicilian family with several patients affected by FAP related to the E109Q mutation, which displayed a somatic mosaicism with the reversion to normality of the c...
May 15, 2017: Human Genetics
https://www.readbyqxmd.com/read/28497172/deep-intronic-mutations-and-human-disease
#11
REVIEW
Rita Vaz-Drago, Noélia Custódio, Maria Carmo-Fonseca
Next-generation sequencing has revolutionized clinical diagnostic testing. Yet, for a substantial proportion of patients, sequence information restricted to exons and exon-intron boundaries fails to identify the genetic cause of the disease. Here we review evidence from mRNA analysis and entire genomic sequencing indicating that pathogenic mutations can occur deep within the introns of over 75 disease-associated genes. Deleterious DNA variants located more than 100 base pairs away from exon-intron junctions most commonly lead to pseudo-exon inclusion due to activation of non-canonical splice sites or changes in splicing regulatory elements...
May 12, 2017: Human Genetics
https://www.readbyqxmd.com/read/28484853/protein-sequestration-as-a-normal-function-of-long-noncoding-rnas-and-a-pathogenic-mechanism-of-rnas-containing-nucleotide-repeat-expansions
#12
REVIEW
Ginny R Morriss, Thomas A Cooper
An emerging class of long noncoding RNAs (lncRNAs) function as decoy molecules that bind and sequester proteins thereby inhibiting their normal functions. Titration of proteins by lncRNAs has wide-ranging effects affecting nearly all steps in gene expression. While decoy lncRNAs play a role in normal physiology, RNAs expressed from alleles containing nucleotide repeat expansions can be pathogenic due to protein sequestration resulting in disruption of normal functions. This review focuses on commonalities between decoy lncRNAs that regulate gene expression by competitive inhibition of protein function through sequestration and specific examples of nucleotide repeat expansion disorders mediated by toxic RNA that sequesters RNA-binding proteins and impedes their normal functions...
May 8, 2017: Human Genetics
https://www.readbyqxmd.com/read/28660352/erratum-to-haploinsufficiency-of-the-e3-ubiquitin-protein-ligase-gene-trip12-causes-intellectual-disability-with-or-without-autism-spectrum-disorders-speech-delay-and-dysmorphic-features
#13
Jing Zhang, Tomasz Gambin, Bo Yuan, Przemyslaw Szafranski, Jill A Rosenfeld, Mohammed Al Balwi, Abdulrahman Alswaid, Lihadh Al-Gazali, Aisha M Al Shamsi, Makanko Komara, Bassam R Ali, Elizabeth Roeder, Laura McAuley, Daniel S Roy, David K Manchester, Pilar Magoulas, Lauren E King, Vickie Hannig, Dominique Bonneau, Anne-Sophie Denommé-Pichon, Majida Charif, Thomas Besnard, Stéphane Bézieau, Benjamin Cogné, Joris Andrieux, Wenmiao Zhu, Weimin He, Francesco Vetrini, Patricia A Ward, Sau Wai Cheung, Weimin Bi, Christine M Eng, James R Lupski, Yaping Yang, Ankita Patel, Seema R Lalani, Fan Xia, Paweł Stankiewicz
No abstract text is available yet for this article.
August 2017: Human Genetics
https://www.readbyqxmd.com/read/28656458/a-genetic-risk-score-is-differentially-associated-with-migraine-with-and-without-aura
#14
Claudia Pisanu, Martin Preisig, Enrique Castelao, Jennifer Glaus, Giorgio Pistis, Alessio Squassina, Maria Del Zompo, Kathleen R Merikangas, Gérard Waeber, Peter Vollenweider, Jessica Mwinyi, Helgi B Schiöth
Although a number of migraine-associated single-nucleotide polymorphisms (SNP) with small effect size have been identified, little is known about the additive impact of these variants on migraine risk, frequency and severity. We investigated to what extent a genetic risk score (GRS) based on recently published, novel migraine-associated SNPs is associated with migraine prevalence, subtypes and severity in a large population-based sample. The sample comprised 446 subjects with migraine and 2511 controls from the CoLaus/PsyCoLaus study...
August 2017: Human Genetics
https://www.readbyqxmd.com/read/28653172/a-cis-eqtl-genetic-variant-of-the-cancer-testis-gene-ccdc116-is-associated-with-risk-of-multiple-cancers
#15
Na Qin, Cheng Wang, Qun Lu, Tongtong Huang, Meng Zhu, Lihua Wang, Fei Yu, Mingtao Huang, Yue Jiang, Juncheng Dai, Hongxia Ma, Guangfu Jin, Chen Wu, Dongxin Lin, Hongbing Shen, Zhibin Hu
Recent studies have found that cancer-testis (CT) genes, which are expressed predominantly in germ and cancer cells, may be candidate cancer drivers. Because of their crucial roles, genetic variants in these genes may contribute to the development of cancer. Here, we systematically evaluated associations of common variants in CT genes and their promoters for the risk of lung cancer in our initial GWAS (2331 cases and 3077 controls), followed by in silico replication using additional 10,512 lung cancer cases and 9562 controls...
August 2017: Human Genetics
https://www.readbyqxmd.com/read/28646452/dosage-effects-of-zp2-and-zp3-heterozygous-mutations-cause-human-infertility
#16
Wenqiang Liu, Kunming Li, Dandan Bai, Jiqing Yin, Yuanyuan Tang, Fengli Chi, Linfeng Zhang, Yu Wang, Jiaping Pan, Shanshan Liang, Yi Guo, Jingling Ruan, Xiaochen Kou, Yanhong Zhao, Hong Wang, Jiayu Chen, Xiaoming Teng, Shaorong Gao
The zona pellucida (ZP) is an extracellular matrix universally surrounding mammalian eggs, which is essential for oogenesis, fertilization, and pre-implantation embryo development. Here, we identified two novel heritable mutations of ZP2 and ZP3, both occurring in an infertile female patient with ZP-abnormal eggs. Mouse models with the same mutations were generated by CRISPR/Cas9 gene editing system, and oocytes obtained from female mice with either single heterozygous mutation showed approximately half of the normal ZP thickness compared to wild-type oocytes...
August 2017: Human Genetics
https://www.readbyqxmd.com/read/28634715/regulatory-element-based-prediction-identifies-new-susceptibility-regulatory-variants-for-osteoporosis
#17
Shi Yao, Yan Guo, Shan-Shan Dong, Ruo-Han Hao, Xiao-Feng Chen, Yi-Xiao Chen, Jia-Bin Chen, Qing Tian, Hong-Wen Deng, Tie-Lin Yang
Despite genome-wide association studies (GWASs) have identified many susceptibility genes for osteoporosis, it still leaves a large part of missing heritability to be discovered. Integrating regulatory information and GWASs could offer new insights into the biological link between the susceptibility SNPs and osteoporosis. We generated five machine learning classifiers with osteoporosis-associated variants and regulatory features data. We gained the optimal classifier and predicted genome-wide SNPs to discover susceptibility regulatory variants...
August 2017: Human Genetics
https://www.readbyqxmd.com/read/28631064/analysis-of-case-parent-trios-for-imprinting-effect-using-a-loglinear-model-with-adjustment-for-sex-of-parent-specific-transmission-ratio-distortion
#18
Lam Opal Huang, Claire Infante-Rivard, Aurélie Labbe
Transmission ratio distortion (TRD) is a phenomenon where parental transmission of disease allele to the child does not follow the Mendelian inheritance ratio. TRD occurs in a sex-of-parent-specific or non-sex-of-parent-specific manner. An offset computed from the transmission probability of the minor allele in control-trios can be added to the loglinear model to adjust for TRD. Adjusting the model removes the inflation in the genotype relative risk (RR) estimate and Type 1 error introduced by non-sex-of-parent-specific TRD...
August 2017: Human Genetics
https://www.readbyqxmd.com/read/28620713/angiopoietin-receptor-tek-interacts-with-cyp1b1-in-primary-congenital-glaucoma
#19
Meha Kabra, Wei Zhang, Sonika Rathi, Anil K Mandal, Sirisha Senthil, Goutham Pyatla, Muralidhar Ramappa, Seema Banerjee, Konegari Shekhar, Srinivas Marmamula, Asha L Mettla, Inderjeet Kaur, Rohit C Khanna, Hemant Khanna, Subhabrata Chakrabarti
Primary congenital glaucoma (PCG) is a severe autosomal recessive ocular disorder associated with considerable clinical and genetic heterogeneity. Recently, rare heterozygous alleles in the angiopoietin receptor-encoding gene TEK were implicated in PCG. We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous TEK mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing...
August 2017: Human Genetics
https://www.readbyqxmd.com/read/28600779/the-landscape-of-genetic-diseases-in-saudi-arabia-based-on-the-first-1000-diagnostic-panels-and-exomes
#20
Dorota Monies, Mohamed Abouelhoda, Moeenaldeen AlSayed, Zuhair Alhassnan, Maha Alotaibi, Husam Kayyali, Mohammed Al-Owain, Ayaz Shah, Zuhair Rahbeeni, Mohammad A Al-Muhaizea, Hamad I Alzaidan, Edward Cupler, Saeed Bohlega, Eissa Faqeih, Maha Faden, Banan Alyounes, Dyala Jaroudi, Ewa Goljan, Hadeel Elbardisy, Asma Akilan, Renad Albar, Hesham Aldhalaan, Shamshad Gulab, Aziza Chedrawi, Bandar K Al Saud, Wesam Kurdi, Nawal Makhseed, Tahani Alqasim, Heba Y El Khashab, Hamoud Al-Mousa, Amal Alhashem, Imaduddin Kanaan, Talal Algoufi, Khalid Alsaleem, Talal A Basha, Fathiya Al-Murshedi, Sameena Khan, Adila Al-Kindy, Maha Alnemer, Sami Al-Hajjar, Suad Alyamani, Hasan Aldhekri, Ali Al-Mehaidib, Rand Arnaout, Omar Dabbagh, Mohammad Shagrani, Dieter Broering, Maha Tulbah, Amal Alqassmi, Maisoon Almugbel, Mohammed AlQuaiz, Abdulaziz Alsaman, Khalid Al-Thihli, Raashda A Sulaiman, Wajeeh Al-Dekhail, Abeer Alsaegh, Fahad A Bashiri, Alya Qari, Suzan Alhomadi, Hisham Alkuraya, Mohammed Alsebayel, Muddathir H Hamad, Laszlo Szonyi, Faisal Abaalkhail, Sulaiman M Al-Mayouf, Hamad Almojalli, Khalid S Alqadi, Hussien Elsiesy, Taghreed M Shuaib, Mohammed Zain Seidahmed, Ibraheem Abosoudah, Hana Akleh, Abdulaziz AlGhonaium, Turki M Alkharfy, Fuad Al Mutairi, Wafa Eyaid, Abdullah Alshanbary, Farrukh R Sheikh, Fahad I Alsohaibani, Abdullah Alsonbul, Saeed Al Tala, Soher Balkhy, Randa Bassiouni, Ahmed S Alenizi, Maged H Hussein, Saeed Hassan, Mohamed Khalil, Brahim Tabarki, Saad Alshahwan, Amira Oshi, Yasser Sabr, Saad Alsaadoun, Mustafa A Salih, Sarar Mohamed, Habiba Sultana, Abdullah Tamim, Moayad El-Haj, Saif Alshahrani, Dalal K Bubshait, Majid Alfadhel, Tariq Faquih, Mohamed El-Kalioby, Shazia Subhani, Zeeshan Shah, Nabil Moghrabi, Brian F Meyer, Fowzan S Alkuraya
In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants...
August 2017: Human Genetics
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