Homozygosity for FARSB mutation leads to Phe-tRNA synthetase-related disease of growth restriction, brain calcification, and interstitial lung disease.

Hum Mutat. 2018 Jul 16;:

Authors: Zadjali F, Al-Yahyaee A, Al-Nabhani M, Al-Mubahesi S, Gujjar A, Raniga S, Al-Maawali A

Abstract
Aminoacyl-tRNA synthetases (ARSs) canonical function is to conjugate specific amino acids to cognate tRNA that are required for the first step of protein synthesis. Genetic mutations that cause dysfunction or absence of ARSs result in various neurodevelopmental disorders. The human phenylalanine-tRNA synthetase (PheRS) is a tetrameric protein made of two a subunits coded by FARSA gene and two b subunits coded by FARSB gene. We describe eight affected individuals from an extended family with a multisystemic recessive disease manifest as a significant growth restriction, brain calcifications, and interstitial lung disease. Genome-wide linkage analysis and whole exome sequencing identified homozygosity for a FARSB mutation (NM_005687.4:c.853G > A:p.Glu285Lys) that co-segregate with the disease and likely cause loss-of-function. This study further implicates FARSB mutations in a multisystem, recessive, neurodevelopmental phenotype that share clinical features with the previously known aminoacyl-tRNA synthetase-related diseases. This article is protected by copyright. All rights reserved.

PMID: 30014610 [PubMed - as supplied by publisher]

Whole-Exome Sequencing in Adults With Chronic Kidney Disease.

Ann Intern Med. 2018 Jul 17;169(2):132-133

Authors: Kiryluk K, Groopman E, Rasouly H, Garcia CK, Gharavi AG

PMID: 30014107 [PubMed - in process]

Whole-Exome Sequencing in Adults With Chronic Kidney Disease.

Ann Intern Med. 2018 Jul 17;169(2):131-132

Authors: Chang AR, Luo JZ, Ho K, Mirshahi T, Murray MF

PMID: 30014106 [PubMed - in process]

Multigenic Disease and Bilineal Inheritance in Dilated Cardiomyopathy Is Illustrated in Nonsegregating LMNA Pedigrees.

Circ Genom Precis Med. 2018 Jul;11(7):e002038

Authors: Cowan JR, Kinnamon DD, Morales A, Salyer L, Nickerson DA, Hershberger RE

Abstract
BACKGROUND: We have previously described 19 pedigrees with apparent lamin (LMNA)-related dilated cardiomyopathy (DCM) manifesting in affected family members across multiple generations. In 6 of 19 families, at least 1 individual with idiopathic DCM did not carry the family's LMNA variant. We hypothesized that additional genetic cause may underlie DCM in these families.
METHODS: Affected family members underwent exome sequencing to identify additional genetic cause of DCM in the 6 families with nonsegregating LMNA variants.
RESULTS: In 5 of 6 pedigrees, we identified at least 1 additional rare variant in a known DCM gene that could plausibly contribute to disease in the LMNA variant-negative individuals. Bilineal inheritance was clear or presumed to be present in 3 of 5 families and was possible in the remaining 2. At least 1 individual with a LMNA variant also carried a variant in an additional identified DCM gene in each family. Using a multivariate linear mixed model for quantitative traits, we demonstrated that the presence of these additional variants was associated with a more severe phenotype after adjusting for sex, age, and the presence/absence of the family's nonsegregating LMNA variant.
CONCLUSIONS: Our data support DCM as a genetically heterogeneous disease with, at times, multigene causation. Although the frequency of DCM resulting from multigenic cause is uncertain, our data suggest it may be higher than previously anticipated.

PMID: 30012837 [PubMed - in process]

COL4A3 Gene Variants and Diabetic Kidney Disease in MODY.

Clin J Am Soc Nephrol. 2018 Jul 16;:

Authors: Wang Y, Zhang J, Zhao Y, Wang S, Zhang J, Han Q, Zhang R, Guo R, Li H, Li L, Wang T, Tang X, He C, Teng G, Gu W, Liu F

Abstract
BACKGROUND AND OBJECTIVES: Despite advances in identifying genetic factors of diabetic kidney disease (DKD), much of the heritability remains unexplained. Nine maturity-onset diabetes in young (MODY) probands with kidney biopsy-proven DKD were selected and included in this study. The probands had more severe DKD compared with their parents with MODY, with overt proteinuria or rapid progression to ESKD. We aimed to explore the contribution of the variants in susceptibility genes of DKD to the severity of kidney phenotype between the probands and their parents.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Whole-exome sequencing was performed to identify suspected MODY probands and their families. Known DKD susceptibility genes were reviewed. Variants reported to be associated with DKD, or those with minor allele frequency <0.05 and predicted to be pathogenic, were selected and analyzed. Immunofluorescence staining of COL4α3 was performed in kidney specimens of patients with DKD with or without R408H and M1209I of COL4A3 variants.
RESULTS: HNF1B-MODY, CEL-MODY, PAX4-MODY, and WFS1-MODY were diagnosed among nine families. We identified 196 selected variants of 25 DKD susceptibility genes among the participants. Analysis of phenotype between probands and parents, gene function, and protein-protein interaction networks revealed that COL4A3 variants were involved in the progression of DKD. Weak granular staining of COL4α3 was observed in the glomerular basement membrane of patients with the R408H and M1209I variants, whereas strong consecutive staining was observed in patients without these variants. Moreover, more number of DKD variants were identified in probands than in their parents with MODY.
CONCLUSIONS: The genetic effect of more pathogenic variants in various DKD susceptibility genes, especially variants in the COL4A3 gene, partially explained the more severe kidney phenotype in probands with kidney biopsy-proven DKD.

PMID: 30012629 [PubMed - as supplied by publisher]

Genetic Contribution to Risk for Diabetic Kidney Disease.

Clin J Am Soc Nephrol. 2018 Jul 16;:

Authors: Rich SS

PMID: 30012628 [PubMed - as supplied by publisher]

Germline and somatic variations influence the somatic mutational signatures of esophageal squamous cell carcinomas in a Chinese population.

BMC Genomics. 2018 Jul 16;19(1):538

Authors: Guo J, Huang J, Zhou Y, Zhou Y, Yu L, Li H, Hou L, Zhu L, Ge D, Zeng Y, Guleng B, Li Q

Abstract
BACKGROUND: Esophageal squamous cell carcinomas (ESCC) is the fourth most lethal cancer in China. Previous studies reveal several highly conserved mutational processes in ESCC. However, it remains unclear what are the true regulators of the mutational processes.
RESULTS: We analyzed the somatic mutational signatures in 302 paired whole-exome sequencing data of ESCC in a Chinese population for potential regulators of the mutational processes. We identified three conserved subtypes based on the mutational signatures with significantly different clinical outcomes. Our results show that patients of different subpopulations of Chinese differ significantly in the activity of the "NpCpG" signature (FDR = 0.00188). In addition, we report ZNF750 and CDC27, of which the somatic statuses and the genetic burdens consistently influence the activities of specific mutational signatures in ESCC: the somatic ZNF750 status is associated with the AID/APOBEC-related mutational process (FDR = 0.0637); the somatic CDC27 copy-number is associated with the "NpCpG" (FDR = 0.00615) and the AID/APOBEC-related mutational processes (FDR = 8.69 × 10- 4). The burdens of germline variants in the two genes also significantly influence the activities of the same somatic mutational signatures (FDR < 0.1).
CONCLUSIONS: We report multiple factors that influence the mutational processes in ESCC including: the subpopulations of Chinese; the germline and somatic statuses of ZNF750 and CDC27 and exposure to alcohol and tobacco. Our findings based on the evidences from both germline and somatic levels reveal potential genetic regulators of the somatic mutational processes and provide insights into the biology of esophageal carcinogenesis.

PMID: 30012096 [PubMed - in process]

Whole-exome sequencing identifies a novel INS mutation causative of maturity-onset diabetes of the young 10.

J Mol Cell Biol. 2017 Oct 01;9(5):376-383

Authors: Yan J, Jiang F, Zhang R, Xu T, Zhou Z, Ren W, Peng D, Liu Y, Hu C, Jia W

Abstract
Monogenic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics. This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type 2 diabetes and to explore potential molecular mechanisms. Whole-exome sequencing was performed on 31 individuals clinically diagnosed with type 2 diabetes. One novel heterozygous mutation (p.Ala2Thr) in INS was identified. It was further genotyped in an additional case-control population (6523 cases and 4635 controls), and this variant was observed in 0.09% of cases. Intracellular trafficking of insulin proteins was assessed in INS1-E and HEK293T cells. p.Ala2Thr preproinsulin-GFP was markedly retained in the endoplasmic reticulum (ER) in INS1-E cells. Activation of the PERK-eIF2α-ATF4, IRE1α-XBP1, and ATF6 pathways as well as upregulated ER chaperones were detected in INS1-E cells transfected with the p.Ala2Thr mutant. In conclusion, we identified a causative mutation in INS responsible for maturity-onset diabetes of the young 10 (MODY10) in a Chinese population and demonstrated that this mutation affected β cell function by inducing ER stress.

PMID: 28992123 [PubMed - indexed for MEDLINE]

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"Rare Diseases"[Mesh] OR "orphan disease"

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Drug repositioning for schizophrenia and depression/anxiety disorders: A machine learning approach leveraging expression data.

IEEE J Biomed Health Inform. 2018 Jul 16;:

Authors: Zhao K, So HC

Abstract
Development of new medications is a lengthy and costly process, and drug repositioning might help to shorten the development cycle. We present a machine learning (ML) workflow to drug discovery or repositioning by predicting indication for a particular disease based on drug expression profiles, with a focus on applications in psychiatry. Drugs that are not originally indicated for the disease but with high predicted probabilities serve as candidates for repurposing. This approach is widely applicable to any chemicals or drugs with expression profiles measured, even if drug targets are unknown. It is also highly flexible as virtually any supervised learning algorithms can be used. We employed the ML approach to identify repositioning opportunities for schizophrenia as well as depression and anxiety disorders. We applied various state-of-the-art ML approaches, including deep neural networks (DNN), support vector machines (SVM), elastic net regression, random forest and gradient boosted trees. The predictive performance of the five approaches in cross-validation did not differ substantially, with SVM slightly outperforming the others. However, other methods also reveal literature-supported repositioning candidates of different mechanisms of actions. As a further validation, we showed that the repositioning hits are enriched for psychiatric medications considered in clinical trials. We also examined the correlation between predicted probabilities of treatment potential and the number of related research articles, and found significant correlations for all methods, especially DNN. Finally, we propose that ML may provide a new avenue to exploring drug mechanisms via examining the variable importance of gene features.

PMID: 30010603 [PubMed - as supplied by publisher]

Drug Repurposing in the Development of Anticancer Agents.

Curr Med Chem. 2018 Jul 13;:

Authors: Olgen S, Kotra L

Abstract
BACKGROUND: Research into repositioning known drugs to treat cancer other than the originally intended disease continues to grow and develop, encouraged in part, by several recent success stories. Many of the studies in this article are geared towards repurposing generic drugs because additional clinical trials are relatively easy to perform and the drug safety profiles have previously been established.
OBJECTIVE: This review provides an overview of anti-cancer drug development strategies which is one of the important areas of drug re-structuring.
METHODS: Repurposed drugs for cancer treatments are classified by their pharmacological effects. The successes and failures of important repurposed drugs as anti-cancer agents are evaluated in this review.
RESULTS AND CONCLUSION: Drugs could have many off-target effects, and can be intelligently repurposed if the off-target effects can be employed for therapeutic purposes. In cancer, due to the heterogeneity of the disease, often targets are quite diverse, hence a number of already known drugs that interfere with these targets could be deployed or repurposed with appropriate research and development.

PMID: 30009698 [PubMed - as supplied by publisher]

Metformin in Idiopathic Pulmonary Fibrosis "Seeking the Holy-Grail through Drug-Repositioning".

Respiration. 2018 Jul 13;:1-3

Authors: Tzouvelekis A, Tzilas V, Dassiou M, Bouros D

PMID: 30007987 [PubMed - as supplied by publisher]