Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis.

J Clin Invest. 2017 Jul 10;:

Authors: Zang S, Li J, Yang H, Zeng H, Han W, Zhang J, Lee M, Moczygemba M, Isgandarova S, Yang Y, Zhou Y, Rao A, You MJ, Sun D, Huang Y

Abstract
Angioimmunoblastic T cell lymphoma (AITL) represents a distinct, aggressive form of peripheral T cell lymphoma with a dismal prognosis. Recent exome sequencing in patients with AITL has revealed the frequent coexistence of somatic mutations in the Rho GTPase RhoA (RhoAG17V) and loss-of-function mutations in the 5-methylcytosine oxidase TET2. Here, we have demonstrated that TET2 loss and RhoAG17V expression in mature murine T cells cooperatively cause abnormal CD4+ T cell proliferation and differentiation by perturbing FoxO1 gene expression, phosphorylation, and subcellular localization, an abnormality that is also detected in human primary AITL tumor samples. Reexpression of FoxO1 attenuated aberrant immune responses induced in mouse models adoptively transferred with T cells and bearing genetic lesions in both TET2 and RhoA. Our findings suggest a mutational cooperativity between epigenetic factors and GTPases in adult CD4+ T cells that may account for immunoinflammatory responses associated with AITL patients.

PMID: 28691928 [PubMed - as supplied by publisher]

Integrating Next-Generation Genomic Sequencing and Mass Spectrometry to Estimate Allele-Specific Protein Abundance in Human Brain.

J Proteome Res. 2017 Jul 10;:

Authors: Wingo TS, Duong DM, Zhou M, Dammer EB, Wu H, Cutler DJ, Lah JJ, Levey AI, Seyfried NT

Abstract
Gene expression contributes to phenotypic traits and human disease. To date, comparatively less is known about regulators of protein abundance, which is also under genetic control and likely influences clinical phenotypes. However, identifying and quantifying allele-specific protein abundance by bottom-up proteomics is challenging since single nucleotide variants (SNVs) that alter protein sequence are not considered in standard human protein databases. To address this, we developed the GenPro software and used it to create personalized protein databases (PPDs) to identify single amino acid variants (SAAVs) at the protein level from whole exome sequencing. In silico assessment of PPDs generated by GenPro revealed only a 1% increase in tryptic search space compared to a direct translation of all human transcripts and an equivalent search space compared to the UniProtKB reference database. To identify a large unbiased number of SAAV peptides, we performed high-resolution mass spectrometry-based proteomics for two human post-mortem brain samples and searched the collected MS/MS spectra against their respective PPD. We found an average of ~117,000 unique peptides mapping to ~9,300 protein groups for each sample and of these 977 were unique variant peptides. We found that over 400 reference and SAAV peptide pairs were, on average, equally abundant in human brain by label-free ion intensity measurements and confirmed the absolute levels of three reference and SAAV peptide pairs using heavy labeled peptides standards coupled with parallel reaction monitoring (PRM). Our results highlight the utility of integrating genomic and proteomic sequencing data to identify sample-specific SAAV peptides and support the hypothesis that most alleles are equally expressed in human brain.

PMID: 28691493 [PubMed - as supplied by publisher]

Next generation sequencing and array-based comparative genomic hybridization for molecular diagnosis of pediatric endocrine disorders.

Ann Pediatr Endocrinol Metab. 2017 Jun;22(2):90-94

Authors: Fukami M, Miyado M

Abstract
Next-generation sequencing (NGS) and array-based comparative genomic hybridization (array CGH) have enabled us to perform high-throughput mutation screening and genome-wide copy number analysis, respectively. These methods can be used for molecular diagnosis of pediatric endocrine disorders. NGS has determined the frequency and phenotypic variation of mutations in several disease-associated genes. Furthermore, whole exome analysis using NGS has successfully identified several novel causative genes for endocrine disorders. Array CGH is currently used as the standard procedure for molecular cytogenetic analysis. Array CGH can detect various submicroscopic genomic rearrangements involving exons or enhancers of disease-associated genes. This review introduces some examples of the use of NGS and array CGH for the molecular diagnosis of pediatric endocrine disorders.

PMID: 28690986 [PubMed]

Whole-exome sequencing analysis of Waardenburg syndrome in a Chinese family.

Hum Genome Var. 2017;4:17027

Authors: Chen D, Zhao N, Wang J, Li Z, Wu C, Fu J, Xiao H

Abstract
Waardenburg syndrome (WS) is a dominantly inherited, genetically heterogeneous auditory-pigmentary syndrome characterized by non-progressive sensorineural hearing loss and iris discoloration. By whole-exome sequencing (WES), we identified a nonsense mutation (c.598C>T) in PAX3 gene, predicted to be disease causing by in silico analysis. This is the first report of genetically diagnosed case of WS PAX3 c.598C>T nonsense mutation in Chinese ethnic origin by WES and in silico functional prediction methods.

PMID: 28690861 [PubMed - in process]

The detection of a novel insertion mutation in exon 2 of the MEFV gene associated with familial mediterranean fever in a moroccan family.

Hum Genome Var. 2017;4:17023

Authors: Mejtoute T, Sayel H, El-Akhal J, Moufid FZ, Bouguenouch L, El Bouchikhi I, Hida M, Couissi D, Ouldim K

Abstract
Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease that is inherited in an autosomal recessive manner and is caused by mutations in the MEFV gene. As the name indicates, FMF occurs within families and is more common in individuals of Mediterranean descent than in persons of any other ethnicity. To date, 314 mutations have been reported. We studied a Moroccan family with a total of five members, including a mother who was presenting with symptoms of FMF, while her four children remained asymptomatic. The five patients were screened by DNA sequencing of exon 2 and exon 10 of the MEFV gene. Then, complete exome sequencing analysis of the MEFV gene was done for the patients in whom a novel mutation was detected. This analysis identified a novel single base Cytosine (C) insertion mutation in the coding region of the MEFV gene, named c.441dupC (p. Glu148Argfs*5 or E148RfsX5), which resulted in a mutated Pyrin/Marenostrin protein. This is the first report of a new mutation in exon 2 of the MEFV gene in a Moroccan family. This novel insertion mutation may provide important information for further studies of FMF pathogenesis.

PMID: 28690860 [PubMed - in process]

[Drug induced angioedema: a rare side effect of simvastatin].

Pan Afr Med J. 2017;26:213

Authors: El Mekki AB, Chaib A

PMID: 28690728 [PubMed - in process]

Notice NOT-OD-17-088 from the NIH Guide for Grants and Contracts

Notice NOT-CA-17-063 from the NIH Guide for Grants and Contracts

Notice NOT-NR-17-020 from the NIH Guide for Grants and Contracts

Notice NOT-MH-17-038 from the NIH Guide for Grants and Contracts

Notice NOT-MH-17-037 from the NIH Guide for Grants and Contracts

GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant.

Neurobiol Dis. 2017 Jul 05;:

Authors: Giddens MM, Wong JC, Schroeder JP, Farrow EG, Smith BM, Owino S, Soden SE, Meyer RC, Saunders C, LePichon JB, Weinshenker D, Escayg A, Hall RA

Abstract
Progressive myoclonus epilepsies (PMEs) are disorders characterized by myoclonic and generalized seizures with progressive neurological deterioration. While several genetic causes for PMEs have been identified, the underlying causes remain unknown for a substantial portion of cases. Here we describe several affected individuals from a large, consanguineous family presenting with a novel PME in which symptoms begin in adolescence and result in death by early adulthood. Whole exome analyses revealed that affected individuals have a homozygous variant in GPR37L1 (c.1047G>T [Lys349Asp]), an orphan G protein-coupled receptor (GPCR) expressed predominantly in the brain. In vitro studies demonstrated that the K349N substitution in GPR37L1 did not grossly alter receptor expression, surface trafficking or constitutive signaling in transfected cells. However, in vivo studies revealed that a complete loss of GPR37L1 function in mice results in increased seizure susceptibility. Mice lacking the related receptor Gpr37 also exhibited an increase in seizure susceptibility, while genetic deletion of both receptors resulted in an even more dramatic increase in vulnerability to seizures. These findings provide evidence linking GPR37L1 and GPR37 to seizure etiology and demonstrate an association between a GPR37L1 variant and a novel progressive myoclonus epilepsy.

PMID: 28688853 [PubMed - as supplied by publisher]

Apoptotic and genotoxic effects of low-intensity ultrasound on healthy and leukemic human peripheral mononuclear blood cells.

J Med Ultrason (2001). 2017 Jul 08;:

Authors: Saliev T, Begimbetova D, Baiskhanova D, Abetov D, Kairov U, Gilman CP, Matkarimov B, Tachibana K

Abstract
PURPOSE: To scrutinize the apoptotic and genotoxic effects of low-intensity ultrasound and an ultrasound contrast agent (SonoVue; Bracco Diagnostics Inc., EU) on human peripheral mononuclear blood cells (PMBCs).
METHODS: PMBCs were subjected to a low-intensity ultrasound field (1-MHz frequency; spatial peak temporal average intensity 0.18 W/cm2) followed by analysis for apoptosis and DNA damage (single-strand breaks + double-strand breaks). The comet assay was then repeated after 2 h to examine the ability of cells to repair DNA breaks.
RESULTS: The results demonstrated that low-intensity ultrasound was capable of selectively inducing apoptosis in leukemic PMBCs, but not in healthy cells. The introduction of ultrasound contrast agent SonoVue resulted in an increase in apoptosis in both groups. DNA analysis after ultrasound exposure indicated that ultrasound triggered DNA damage in leukemic PMBCs (66.05 ± 13.36%), while the damage was minimal (7.01 ± 0.89%) in control PMBCs. However, both cell lines demonstrated an ability to repair DNA single- and double-strand breaks 2 h after sonication.
CONCLUSIONS: The study demonstrated that low-intensity ultrasound selectively induced apoptosis in cancer PMBCs. Ultrasound-induced DNA damage was observed primarily in leukemic PMBCs. Nevertheless, both cell lines were able to repair ultrasound-mediated DNA strand breaks.

PMID: 28689300 [PubMed - as supplied by publisher]

Notice NOT-OD-17-085 from the NIH Guide for Grants and Contracts

Notice NOT-DK-17-014 from the NIH Guide for Grants and Contracts

Notice NOT-NR-17-022 from the NIH Guide for Grants and Contracts

Notice NOT-CA-17-054 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-17-325 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites Research Project Grant (R01) applications that propose to study the ethical, legal and social implications (ELSI) of human genome research. Applications may propose studies using either single or mixed methods. Proposed approaches may include but are not limited to data-generating qualitative and quantitative approaches, legal, economic and normative analyses, and other types of analytical and conceptual research methodologies, such as those involving the direct engagement of stakeholders.

Funding Opportunity PA-17-324 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites Small Research Grant (R03) applications to study the ethical, legal and social implications (ELSI) of human genome research. These applications should be for small, self-contained research projects, such as those that involve single investigators. Of particular interest are projects that propose normative or conceptual analyses, including focused legal, economic, philosophical, anthropological, or historical analyses of new or emerging issues. This mechanism can also be used for the collection of preliminary data and the secondary analysis of existing data.

Funding Opportunity PA-17-323 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites Exploratory/Developmental Research Grant (R21) applications that propose to study the ethical, legal and social implications (ELSI) of human genome research. These applications should propose single or mixed methods studies that break new ground, extend previous discoveries in new directions or develop preliminary data in preparation for larger studies. Of particular interest are studies that explore the implications of new or emerging genomic technologies or novel uses of genomic information.