[Molecular aspects of vasoprotective peptide KED activity during atherosclerosis and restenosis].

Adv Gerontol. 2016;29(4):646-650

Authors: Kozlov KL, Bolotov II, Linkova NS, Drobintseva AO, Khavinson VK, Dyakonov MM, Kozina LS

Abstract
Peptide KED (Lys-Glu-Asp) has vasoprotective effects and is effective substance in treatment of of atherosclerosis and other cardio-vascular disorders in elderly people. One of the probable mechanisms of biological activity of this peptide is epigenetic genes regulation. These genes can coding proteins, which are markers of endothelium functional activity. The goal of investigation was to study the KED peptide effect on signal molecules expression in normal, atherosclerotic and restenotic endothelium in vitro. It was shown, that KED peptide has normalized endothelin-1 expression, which increased during atherosclerosis and restenosis. KED peptide also restorates cells interactions by connexin expression. Geroprotective effect of KED peptide is realized by increasing of sirtuin1 expression, which has took part in DNA reparation.

PMID: 28539025 [PubMed - indexed for MEDLINE]

Antisense inhibitors retain activity in pulmonary models of Burkholderia infection.

ACS Infect Dis. 2018 Feb 20;:

Authors: Daly SM, Sturge CR, Marshall-Batty KR, Felder-Scott CF, Jain R, Geller B, Greenberg D

Abstract
The Burkholderia cepacia complex is a group of gram-negative bacteria that are opportunistic pathogens in immunocompromised individuals, such as those with cystic fibrosis (CF) or chronic granulomatous disease (CGD). Burkholderia are intrinsically resistant to many antibiotics and the lack of antibiotic development necessitates novel therapeutics. Peptide-conjugated phosphorodiamidate morpholino oligomers are antisense molecules that inhibit bacterial mRNA translation. Targeting of PPMOs to the gene acpP, which is essential for membrane synthesis, lead to defects in the membrane and ultimately bactericidal activity. Exploration of additional PPMO sequences identified the ATG and Shine-Dalgarno sites as the most efficacious for targeting acpP. The CF lung is a complex microenvironment, but PPMO inhibition was still efficacious in an artificial model of CF sputum. PPMOs had low toxicity in human CF cells at doses that were antibacterial. PPMOs also reduced the bacterial burden in the lungs of immunocompromised CyBB mice, a model of CGD. Finally, the use of multiple PPMOs was efficacious in inhibiting the growth of both Burkholderia and Pseudomonas in an in vitro model of co-infection. Due to the intrinsic resistance of Burkholderia to traditional antibiotics, PPMOs represent a novel and viable approach to the treatment of Burkholderia infections.

PMID: 29461800 [PubMed - as supplied by publisher]

Metabolomic responses to lumacaftor/ivacaftor in cystic fibrosis.

Pediatr Pulmonol. 2018 Feb 20;:

Authors: Kopp BT, McCulloch S, Shrestha CL, Zhang S, Sarzynski L, Woodley FW, Hayes D

Abstract
BACKGROUND: Cystic fibrosis (CF) is a life-limiting disease caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Lumacaftor/Ivacaftor is a novel CFTR modulator approved for patients that are homozygous for Phe508del CFTR, but its clinical effectiveness varies amongst patients, making it difficult to determine clinical responders. Therefore, identifying biochemical biomarkers associated with drug response are clinically important for follow-up studies.
METHODS: Serum metabolomics was performed on twenty patients with CF pre- and 6-month post-Lumacaftor/Ivacaftor response via Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS). Correlation with clinical variables was performed.
RESULTS: Metabolomics analysis demonstrated 188 differentially regulated metabolites between patients pre- and post-Lumacaftor/Ivacaftor initiation, with a predominance of lipid and amino acid alterations. The top 30 metabolites were able to differentiate pre- and post-Lumacaftor/Ivacaftor status in greater than 90% of patients via a random-forest confusion matrix. Alterations in bile acids, phospholipids, and bacteria-associated metabolites were the predominant changes associated with drug response. Importantly, changes in metabolic patterns were associated with clinical responders.
CONCLUSIONS: Selected key lipid and amino acid metabolic pathways were significantly affected by Lumacaftor/Ivacaftor initiation and similar pathways were affected in clinical responders. Targeted metabolomics may provide useful and relevant biomarkers of CFTR modulator responses.

PMID: 29461009 [PubMed - as supplied by publisher]

Effect of high dose vitamin D3 therapy on serum vitamin D3 levels in vitamin D insufficient adults with cystic fibrosis.

Clin Nutr ESPEN. 2018 Feb;23:84-88

Authors: Regalado Lam Chew Tun R, Porhownik N, Taback S, Oleschuk C

Abstract
BACKGROUND: The effect of a high dose oral cholecalciferol repletion strategy in Vitamin D insufficient adults with CF is still unknown. Therefore, we assessed the effectiveness of our current approach, giving oral vitamin D3 supplementation at a dose of 10,000 IU from Monday to Friday for a total of 50,000 IU D3 weekly in vitamin D insufficient adult with CF.
METHODS: We performed a retrospective chart review of all 59 adult CF patients between the ages of 17 and 64 years routinely followed at the CF Adult Program of Winnipeg Health Sciences Centre. Through consultation with the endocrinologist, our clinic vitamin D repletion protocol for treating CF adult patients who have serum 25-hydroxyvitamin D (25-OHD) < 30 ng/ml (<75 nmol/L) was to prescribe vitamin D3 10,000 IU orally from Monday to Friday (or the weekly equivalent of 50,000 IU) for 12 weeks in addition to their regular CF vitamin that supplied from 800 to 2000 IU vitamin D3 daily. Cholecalciferol was conveniently administered orally as either one capsule (oil-based) 10,000 IU or one tablet (powder-based) 10,000 IU. All patients were instructed to obtain follow-up serum 25-OHD levels post completion of treatment.
RESULTS: Of the 59 adult patients at our CF Clinic, 35 patients (59%) had below optimal serum 25-OHD levels. Of the 35 patients identified, 10 patients with insufficient serum 25-OHD levels between 10 and 30 ng/ml (25-75 nmol/L) fulfilled the inclusion criteria. A significant increase in serum 25-OHD levels was observed (P < 0.01) from mean value of 21.6 ± 5.9 ng/ml (54.1 ± 14.8 nmol/L) at baseline to 31.7 ± 9.1 ng/ml (79.3 ± 22.8 nmol/L) ≥ 2 months post intervention. The current treatment approach was successful in treating Vitamin D insufficiency in 70% of the patients with low 25-OHD levels.
CONCLUSION: The results of this study demonstrate that a large number of adults attending Winnipeg Health Sciences Centre CF Clinic have serum 25-OHD levels below 30 ng/ml (75 nmol/L). This supports the need for dedicated and individualized approach to manage this condition. High dose therapy of vitamin D3, although a more aggressive treatment approach, may result in achieving optimal levels of serum 25-OHD in adults with CF.

PMID: 29460819 [PubMed - in process]

Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator and Drugs: Insights from Cellular Trafficking.

Handb Exp Pharmacol. 2018 Feb 20;:

Authors: Bridges RJ, Bradbury NA

Abstract
The eukaryotic cell is organized into membrane-delineated compartments that are characterized by specific cadres of proteins sustaining biochemically distinct cellular processes. The appropriate subcellular localization of proteins is key to proper organelle function and provides a physiological context for cellular processes. Disruption of normal trafficking pathways for proteins is seen in several genetic diseases, where a protein's absence for a specific subcellular compartment leads to organelle disruption, and in the context of an individual, a disruption of normal physiology. Importantly, several drug therapies can also alter protein trafficking, causing unwanted side effects. Thus, a deeper understanding of trafficking pathways needs to be appreciated as novel therapeutic modalities are proposed. Despite the promising efficacy of novel therapeutic agents, the intracellular bioavailability of these compounds has proved to be a potential barrier, leading to failures in treatments for various diseases and disorders. While endocytosis of drug moieties provides an efficient means of getting material into cells, the subsequent release and endosomal escape of materials into the cytosol where they need to act has been a barrier. An understanding of cellular protein/lipid trafficking pathways has opened up strategies for increasing drug bioavailability. Approaches to enhance endosomal exit have greatly increased the cytosolic bioavailability of drugs and will provide a means of investigating previous drugs that may have been shelved due to their low cytosolic concentration.

PMID: 29460152 [PubMed - as supplied by publisher]

Point shear wave elastography of the pancreas in patients with cystic fibrosis: a comparison with healthy controls.

Abdom Radiol (NY). 2018 Feb 19;:

Authors: Pfahler MHC, Kratzer W, Leichsenring M, Graeter T, Schmidt SA, Wendlik I, Lormes E, Schmidberger J, Fabricius D

Abstract
PURPOSE: Manifestations of cystic fibrosis in the pancreas are gaining in clinical importance as patients live longer. Conventional ultrasonography and point shear wave elastography (pSWE) imaging are non-invasive and readily available diagnostic methods that are easy to perform. The aim of this study was to perform conventional ultrasonography and obtain pSWE values in the pancreases of patients with cystic fibrosis and to compare the findings with those of healthy controls.
METHODS: 27 patients with cystic fibrosis (13 women/14 men; mean age 27.7 ± 13.7 years; range 9-58 years) and 60 healthy control subjects (30 women/30 men; mean age 30.3 ± 10.0 years; range 22-55 years) underwent examinations of the pancreas with conventional ultrasound and pSWE imaging.
RESULTS: Patients with cystic fibrosis have an echogenic pancreatic parenchyma. We found cystic lesions of the pancreas in six patients. pSWE imaging of the pancreatic parenchyma gave significantly lower shear wave velocities in patients with cystic fibrosis than in the control group (1.01 m/s vs 1.30 m/s; p < 0.001).
CONCLUSIONS: Using pSWE imaging in vivo, we have shown that the pancreas is considerably softer in patients with cystic fibrosis than in a healthy control population.

PMID: 29460047 [PubMed - as supplied by publisher]

The pharmacist's role in supporting people living with cystic fibrosis.

J Am Pharm Assoc (2003). 2018 Feb 16;:

Authors: Abraham O, Li JS, Monangai KE, Feathers AM, Weiner D

Abstract
OBJECTIVES: To describe the critical need for pharmacists' involvement in outpatient care for people living with cystic fibrosis (CF).
DATA SOURCES: Not applicable.
SUMMARY: CF is a pulmonary condition that affects more than 30,000 children and adults in the United States and 70,000 people worldwide. Various complex medication regimens are given to patients with CF, some depending on the type of mutation they have in their CF transmembrane conductance regulator protein. With complex medication regimens and the increased number and variety of treatments that have become available, the medication use burden intensifies for individuals living with CF and their caregivers. Young people living with CF have a particularly difficult time adhering to medications and other therapies as they begin to rely less on their caregivers and assume greater medication management responsibility for their care. Adolescents report low adherence rates from about 40% to 47% for airway clearance methods and even lower for nutritional recommendations, about 16% to 20%. In inpatient settings, pharmacists have been successful in making medication use recommendations that have improved adherence for patients with CF while in the hospital. However, limited research has explored how provision of pharmacist supportive care and patient education in outpatient settings can improve medication adherence and quality of life for people living with CF.
CONCLUSION: There is potential for provision of outpatient pharmacy clinical services to increase medication adherence and overall quality of care for patients with CF. Higher rates of medication adherence in patients with CF could in turn improve patient outcomes and reduce overall health care costs as a result of fewer rehospitalizations. Pharmacies can implement programs designed to provide comprehensive support services and medication management from pharmacists and staff that are trained in CF care.

PMID: 29459095 [PubMed - as supplied by publisher]

Molecular characterization of gene regulatory networks in primary human tracheal and bronchial epithelial cells.

J Cyst Fibros. 2018 Feb 17;:

Authors: Gillen AE, Yang R, Cotton CU, Perez A, Randell SH, Leir SH, Harris A

Abstract
BACKGROUND: Robust methods to culture primary airway epithelial cells were developed several decades ago and these cells provide the model of choice to investigate many diseases of the human lung. However, the molecular signature of cells from different regions of the airway epithelium has not been well characterized.
METHODS: We utilize DNase-seq and RNA-seq to examine the molecular signatures of primary cells derived from human tracheal and bronchial tissues, as well as healthy and diseased (cystic fibrosis (CF)) donor lung tissue.
RESULTS: Our data reveal an airway cell signature that is divergent from other epithelial cell types and from common airway epithelial cell lines. The differences between tracheal and bronchial cells are clearly evident as are common regulatory features. Only minor variation is seen between bronchial cells from healthy or CF donors.
CONCLUSIONS: These data are a valuable resource for functional genomics analysis of airway epithelial tissues in human disease.

PMID: 29459038 [PubMed - as supplied by publisher]

First report of a cross-kingdom pathogenic bacterium, Achromobacter xylosoxidans isolated from stipe-rot Coprinus comatus.

Microbiol Res. 2018 Mar;207:249-255

Authors: Ye L, Guo M, Ren P, Wang G, Bian Y, Xiao Y, Zhou Y

Abstract
Coprinus comatus is an edible mushroom widely cultivated in China as a delicious food. Various diseases have occurred on C. comatus with the cultivated area increasing. In this study, the pathogenic bacterium JTG-B1, identified as Achromobacter xylosoxidans by 16S rDNA and nrdA gene sequencing, was isolated from edible mushroom Coprinus comatus with serious rot disease on its stipe. A. xylosoxidans has been confirmed as an important opportunistic human pathogenic bacterium and has been isolated from respiratory samples from cystic fibrosis. It is widely distributed in the environment. Here, we first report that fungi can also serve as a host for A. xylosoxidans. We confirmed that it can cross-kingdom infect between animals (mice) and fungi (C. comatus). The results of pathogenicity tests, physiological, biochemical and genotyping analysis of A. xylosoxidans from different hosts suggested that different strain of A. xylosoxidans may have pathogenicity differentiation. A. xylosoxidans not only is pathogenic to C. comatus but also may threaten human health.

PMID: 29458861 [PubMed - in process]

A Novel Family of Small Molecules that Enhance the Intracellular Delivery and Pharmacological Effectiveness of Antisense and Splice Switching Oligonucleotides.

ACS Chem Biol. 2017 Aug 18;12(8):1999-2007

Authors: Wang L, Ariyarathna Y, Ming X, Yang B, James LI, Kreda SM, Porter M, Janzen W, Juliano RL

Abstract
The pharmacological effectiveness of oligonucleotides has been hampered by their tendency to remain entrapped in endosomes, thus limiting their access to cytosolic or nuclear targets. We have previously reported a group of small molecules that enhance the effects of oligonucleotides by causing their release from endosomes. Here, we describe a second novel family of oligonucleotide enhancing compounds (OECs) that is chemically distinct from the compounds reported previously. We demonstrate that these molecules substantially augment the actions of splice switching oligonucleotides (SSOs) and antisense oligonucleotides (ASOs) in cell culture. We also find enhancement of SSO effects in a murine model. These new compounds act by increasing endosome permeability and causing partial release of entrapped oligonucleotides. While they also affect the permeability of lysosomes, they are clearly different from typical lysosomotropic agents. Current members of this compound family display a relatively narrow window between effective dose and toxic dose. Thus, further improvements are necessary before these agents can become suitable for therapeutic use.

PMID: 28703575 [PubMed - indexed for MEDLINE]

Sex Differences in Inflammatory Response and Acid-Base Balance in Prepubertal Children with Severe Sepsis.

Shock. 2017 Apr;47(4):422-428

Authors: Lefèvre N, Noyon B, Biarent D, Corazza F, Duchateau J, Casimir G

Abstract
PURPOSE AND METHODS: The severity and prognosis of various acute inflammatory conditions, such as sepsis, differ between males and females. The mechanisms underlying these sex differences probably involve both hormonal and genetic factors. In order to evaluate a possible genetic influence, we reviewed clinical signs and biological inflammatory markers of prepubertal children with severe sepsis admitted to the pediatric intensive care unit (PICU).
FINDINGS: A total of 142 prepubertal children, 66 girls and 76 boys, suffering from severe sepsis and admitted to the PICU were included. The survival rate demonstrated a tendency to be higher in females (P = 0.14). Maximum white blood cell count (23,800 cells/μL [15,110-34,600] in girls vs. 19,025 cells/μL [12,358-26,098] in boys, P = 0.02), neutrophil count (16,944 cells/μL [10,620-27,540] vs. 13,756 cells/μL [8410-20,110], P = 0.03), and C-reactive protein level (26.2 mg/dL [15.7-33.6] vs. 18.8 mg/dL [11.1-30.0], P = 0.04) were all significantly higher in girls. Girls also exhibited significantly longer fever duration (2 days [1-6] vs. 1 day [1-3] for the boys, P <0.01), lower pH on admission (7.32 [7.25-7.39] vs. 7.37 [7.31-7.43] P = 0.03), and lower base excess (-6 mEq/L [-10.7 to -0.8] vs. -2.3 mEq/L [-6.6 to -2.6], P <0.01), as well as lower bicarbonate levels (19.1 mEq/l [15.9-24.0] vs. 21.15 mEq/l [18.3-26.68], P = 0.04), when compared with the boys.
CONCLUSIONS: Our study revealed higher neutrophilic inflammation, as well as lower pH on admission, in girls with severe sepsis; associated with longer fever duration, which could contribute to better pathogen clearance. However, further studies are needed to demonstrate the link between acidosis and modulation of the immune response.

PMID: 27755508 [PubMed - indexed for MEDLINE]

CYP3A4 mutation causes vitamin D-dependent rickets type 3.

J Clin Invest. 2018 Feb 20;:

Authors: Roizen JD, Li D, O'Lear L, Javaid MK, Shaw NJ, Ebeling PR, Nguyen HH, Rodda CP, Thummel KE, Thacher TD, Hakonarson H, Levine MA

Abstract
Genetic forms of vitamin D-dependent rickets (VDDRs) are due to mutations impairing activation of vitamin D or decreasing vitamin D receptor responsiveness. Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D. Neither patient had a mutation in any genes known to cause VDDR, however, using whole exome sequence analysis we identified a recurrent de novo missense mutation c.902T>C (p.I301T) in CYP3A4 in both subjects that alters the conformation of substrate-recognition-site 4 (SRS-4). In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold greater activity than wild-type CYP3A4 and 2-fold greater activity than CYP24A1, the principal inactivator of vitamin D metabolites. As CYP3A4 mutations have not previously been linked to rickets, these findings provide new insight into vitamin D metabolism, and demonstrate that accelerated inactivation of vitamin D metabolites represents a previously undescribed mechanism for vitamin D deficiency.

PMID: 29461981 [PubMed - as supplied by publisher]

Genetic Analyses Identified a SALL4 Gene Mutation Associated with Holt-Oram Syndrome.

DNA Cell Biol. 2018 Feb 20;:

Authors: Li B, Chen S, Sun K, Xu R, Wu Y

Abstract
Holt-Oram syndrome (HOS) is an autosomal dominant disorder, which is characterized by deformities of upper limbs and congenital heart defects. Alterations of TBX5 gene have been identified to be the leading cause of HOS, while some cases could not be explained by TBX5 mutations. In our study, we preliminarily diagnosed a newborn baby, who had Tetralogy of Fallot, thumb agenesis, facial dysplasia, and right ear canal malformation, as HOS. Chromosome microarray analyses showed no pathological deletions or replications of chromosome segments; whole exome sequencing screened out six candidate genes that were involved in cardiac diseases or syndromes among which SALL4 has been reported as HOS related gene. We evaluated the pathogenicity of SALL4 mutant sites by series of software. The results indicated that SALL4-M143V may be a polymorphism site, and SALL4-R418C could cause disease. HOPE and SWISS PDB viewer showed that SALL4-R418C leads to changes in amino acid properties, loss of protein hydrogen bond, and functional impact of SALL4 zinc finger domain. These results further confirmed the pathogenic significance of SALL4-R418C mutant. When genetic analyses coupled with bioinformatic analyses, we identified a SALL4 gene rare mutation which might contribute to a newborn with HOS. Although some doubts need to be further discussed and explored, our study deepened the understanding of phenotype difference among syndromes and role of SALL4 mutations in disease occurrence.

PMID: 29461882 [PubMed - as supplied by publisher]

Text-mined phenotype annotation and vector-based similarity to improve identification of similar phenotypes and causative genes in monogenic disease patients.

Hum Mutat. 2018 Feb 20;:

Authors: Saklatvala JR, Dand N, Simpson MA

Abstract
The genetic diagnosis of rare monogenic diseases using exome/genome sequencing requires the true causal variant(s) to be identified from tens of thousands of observed variants. Typically a virtual gene panel approach is taken whereby only variants in genes known to cause phenotypes resembling the patient under investigation are considered. With the number of known monogenic gene-disease pairs exceeding 5000, manual curation of personalised virtual panels using exhaustive knowledge of the genetic basis of the human monogenic phenotypic spectrum is challenging. We present improved probabilistic methods for estimating phenotypic similarity based on Human Phenotype Ontology annotation. A limitation of existing methods for evaluating a disease's similarity to a reference set is that reference diseases are typically represented as a series of binary (present/absent) observations of phenotypic terms. We evaluate a quantified disease reference set, using term frequency in phenotypic text descriptions to approximate term relevance. We demonstrate an improved ability to identify related diseases through the use of a quantified reference set, and that vector space similarity measures perform better than established information content-based measures. These improvements enable the generation of bespoke virtual gene panels, facilitating more accurate and efficient interpretation of genomic variant profiles from individuals with rare Mendelian disorders. These methods are available online at https://atlas.genetics.kcl.ac.uk/~jake/cgi-bin/patient_sim.py This article is protected by copyright. All rights reserved.

PMID: 29460986 [PubMed - as supplied by publisher]

Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.

Clin Genet. 2018 Feb 20;:

Authors: Sébastien M, Ange-Line B, Mirna A, Martin C, Elisabeth S, Cyril G, Anne-Marie G, Aude C, Perrine C, Delphine H, Anne F, Nada H, Antonio V, Frédéric TM, Christophe P, Yannis D, Christel TR, Laurence F

Abstract
Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in OMIM genes and non-OMIM genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients, in order to identity novel MH-ID genes. Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes PSD-95, a protein expressed in various tissues including the brain. In neurons, PSD-95 is localized at the post-synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one for a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients showed mild-to-moderate ID, similar marfanoid features, including a long face, high arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus). Our study emphasizes the role of DLG4 as a novel post-synaptic-associated gene involved in syndromic ID associated with MH.

PMID: 29460436 [PubMed - as supplied by publisher]

Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study.

Ann Intern Med. 2018 Feb 20;168(4):308

Authors:

PMID: 29459969 [PubMed - in process]

Rare deleterious variants in GRHL3 are associated with human spina bifida.

Hum Mutat. 2017 Jun;38(6):716-724

Authors: Lemay P, De Marco P, Emond A, Spiegelman D, Dionne-Laporte A, Laurent S, Merello E, Accogli A, Rouleau GA, Capra V, Kibar Z

Abstract
Neural tube defects, including spina bifida, are among the most common birth defects caused by failure of neural tube closure during development. They have a complex etiology involving largely undetermined environmental and genetic factors. Previous studies in mouse models have implicated the transcription factor Grhl3 as an important factor in the pathogenesis of spina bifida. In the present study, we conducted a resequencing analysis of GRHL3 in a cohort of 233 familial and sporadic cases of spina bifida. We identified two novel truncating variants: one homozygous frameshift variant, p.Asp16Aspfs*10, in two affected siblings and one heterozygous intronic splicing variant, p.Ala318Glyfs*26. We also identified five missense variants, one of which was demonstrated to reduce the activation of gene targets in a luciferase reporter assay. With the previously identified p.Arg391Cys variant, eight variants were found in GRHL3. Comparison of the variant rate between our cohort and the ExAC database identified a significant enrichment of deleterious variants in GRHL3 in the whole gene and the transactivation region in spina bifida patients. These data provide strong evidence for a role of GRHL3 as a predisposing factor to spina bifida and will help dissect the complex etiology and pathogenic mechanisms of these malformations.

PMID: 28276201 [PubMed - indexed for MEDLINE]

Identification and functional analysis of a novel LHX1 mutation associated with congenital absence of the uterus and vagina.

Oncotarget. 2017 Jan 31;8(5):8785-8790

Authors: Zhang W, Zhou X, Liu L, Zhu Y, Liu C, Pan H, Xing Q, Wang J, Wang X, Zhang X, Cao Y, Wang B

Abstract
Congenital absence of the uterus and vagina (CAUV) is the most extreme female Müllerian duct abnormality. Several researches proposed that genetic factors contributed to this disorder, whereas the precise genetic mechanism is far from full elucidation. Here, utilizing whole-exome sequencing (WES), we identified one novel missense mutation in LHX1 (NM_005568: c.G1108A, p.A370T) in one of ten unrelated patients diagnosed with CAUV. This mutation was absent from public databases and our internal database. Through the luciferase reporter analysis, we found that the mutation could change the transcriptional activity of LHX1 and its effect on the regulation of the downstream target gene GSC, which might be associated with urogenital system development. In short, we concluded that the LHX1 may be a pathogenic gene of CAUV. Our results demonstrate the power of whole exome sequencing and gene prioritization approach as diagnostic tools in clinical practice that help make genetic diagnosis of CAUV.

PMID: 28061432 [PubMed - indexed for MEDLINE]

Esophageal cancer in high-risk areas of China: research progress and challenges.

Ann Epidemiol. 2017 Mar;27(3):215-221

Authors: Lin Y, Totsuka Y, Shan B, Wang C, Wei W, Qiao Y, Kikuchi S, Inoue M, Tanaka H, He Y

Abstract
PURPOSE: The extremely high incidence of esophageal cancer in certain rural areas of China has prompted significant intellectual curiosity and research efforts both in China and abroad.
METHODS: We summarize the research progress over the past several decades in high-risk areas (Linxian, Cixian, Shexian, and Yanting) based on literature research and our field trip (2012-2013).
RESULTS: Considerable progress in clarifying the environmental risk factors and pathogenesis of esophageal cancer in high-risk areas has been achieved over the past several decades. Epidemiologic evidence suggests that carcinogen exposure and nutritional deficiency, rather than smoking and drinking, may be the major risk factors for esophageal cancer in the Taihang Mountains region, where the incidence of esophageal cancer is among the highest in the world. Two genome-wide association studies have identified variants in PLCE1 at 10q23 that are significantly associated with esophageal cancer risk. Recent whole-exome studies have revealed a comprehensive mutation pattern, in which the C>T transition is the predominant mutation type.
CONCLUSIONS: Despite extensive research, the main causative factors that contribute to esophageal cancer in high-risk areas have not yet been elucidated. Challenges in this research area include determining the causative role of nitrosamine, identifying other potential carcinogens, and conducting fruitful international collaborative studies based on a multidisciplinary approach. Increased international collaboration will contribute to a better understanding of the etiology of esophageal cancer.

PMID: 28007352 [PubMed - indexed for MEDLINE]