@article {894, title = {Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.}, journal = {Genome Med}, volume = {13}, year = {2021}, month = {2021 04 21}, pages = {66}, abstract = {

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.

RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.

CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

}, keywords = {Adult, Aged, Aged, 80 and over, Angiotensin-Converting Enzyme 2, Asthma, Bronchi, Cardiovascular Diseases, COVID-19, Gene Expression, Genetic Variation, Humans, Middle Aged, Obesity, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, Respiratory Mucosa, Risk Factors, SARS-CoV-2, Smoking}, issn = {1756-994X}, doi = {10.1186/s13073-021-00866-2}, author = {Kasela, Silva and Ortega, Victor E and Martorella, Molly and Garudadri, Suresh and Nguyen, Jenna and Ampleford, Elizabeth and Pasanen, Anu and Nerella, Srilaxmi and Buschur, Kristina L and Barjaktarevic, Igor Z and Barr, R Graham and Bleecker, Eugene R and Bowler, Russell P and Comellas, Alejandro P and Cooper, Christopher B and Couper, David J and Criner, Gerard J and Curtis, Jeffrey L and Han, MeiLan K and Hansel, Nadia N and Hoffman, Eric A and Kaner, Robert J and Krishnan, Jerry A and Martinez, Fernando J and McDonald, Merry-Lynn N and Meyers, Deborah A and Paine, Robert and Peters, Stephen P and Castro, Mario and Denlinger, Loren C and Erzurum, Serpil C and Fahy, John V and Israel, Elliot and Jarjour, Nizar N and Levy, Bruce D and Li, Xingnan and Moore, Wendy C and Wenzel, Sally E and Zein, Joe and Langelier, Charles and Woodruff, Prescott G and Lappalainen, Tuuli and Christenson, Stephanie A} } @article {837, title = {The impact of sex on gene expression across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37\% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.

}, keywords = {Chromosomes, Human, X, Disease, Epigenesis, Genetic, Female, Gene Expression, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans, Male, Organ Specificity, Promoter Regions, Genetic, Quantitative Trait Loci, Sex Characteristics, Sex Factors}, issn = {1095-9203}, doi = {10.1126/science.aba3066}, author = {Oliva, Meritxell and Mu{\~n}oz-Aguirre, Manuel and Kim-Hellmuth, Sarah and Wucher, Valentin and Gewirtz, Ariel D H and Cotter, Daniel J and Parsana, Princy and Kasela, Silva and Balliu, Brunilda and Vi{\~n}uela, Ana and Castel, Stephane E and Mohammadi, Pejman and Aguet, Francois and Zou, Yuxin and Khramtsova, Ekaterina A and Skol, Andrew D and Garrido-Mart{\'\i}n, Diego and Reverter, Ferran and Brown, Andrew and Evans, Patrick and Gamazon, Eric R and Payne, Anthony and Bonazzola, Rodrigo and Barbeira, Alvaro N and Hamel, Andrew R and Martinez-Perez, Angel and Soria, Jos{\'e} Manuel and Pierce, Brandon L and Stephens, Matthew and Eskin, Eleazar and Dermitzakis, Emmanouil T and Segr{\`e}, Ayellet V and Im, Hae Kyung and Engelhardt, Barbara E and Ardlie, Kristin G and Montgomery, Stephen B and Battle, Alexis J and Lappalainen, Tuuli and Guig{\'o}, Roderic and Stranger, Barbara E} } @article {834, title = {RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares.}, journal = {N Engl J Med}, volume = {383}, year = {2020}, month = {2020 07 16}, pages = {218-228}, abstract = {

BACKGROUND: Rheumatoid arthritis, like many inflammatory diseases, is characterized by episodes of quiescence and exacerbation (flares). The molecular events leading to flares are unknown.

METHODS: We established a clinical and technical protocol for repeated home collection of blood in patients with rheumatoid arthritis to allow for longitudinal RNA sequencing (RNA-seq). Specimens were obtained from 364 time points during eight flares over a period of 4 years in our index patient, as well as from 235 time points during flares in three additional patients. We identified transcripts that were differentially expressed before flares and compared these with data from synovial single-cell RNA-seq. Flow cytometry and sorted-blood-cell RNA-seq in additional patients were used to validate the findings.

RESULTS: Consistent changes were observed in blood transcriptional profiles 1 to 2 weeks before a rheumatoid arthritis flare. B-cell activation was followed by expansion of circulating CD45-CD31-PDPN+ preinflammatory mesenchymal, or PRIME, cells in the blood from patients with rheumatoid arthritis; these cells shared features of inflammatory synovial fibroblasts. Levels of circulating PRIME cells decreased during flares in all 4 patients, and flow cytometry and sorted-cell RNA-seq confirmed the presence of PRIME cells in 19 additional patients with rheumatoid arthritis.

CONCLUSIONS: Longitudinal genomic analysis of rheumatoid arthritis flares revealed PRIME cells in the blood during the period before a flare and suggested a model in which these cells become activated by B cells in the weeks before a flare and subsequently migrate out of the blood into the synovium. (Funded by the National Institutes of Health and others.).

}, keywords = {Adult, Arthritis, Rheumatoid, B-Lymphocytes, Female, Fibroblasts, Flow Cytometry, Gene Expression, Humans, Male, Mesenchymal Stem Cells, Middle Aged, Patient Acuity, Sequence Analysis, RNA, Surveys and Questionnaires, Symptom Flare Up, Synovial Fluid}, issn = {1533-4406}, doi = {10.1056/NEJMoa2004114}, author = {Orange, Dana E and Yao, Vicky and Sawicka, Kirsty and Fak, John and Frank, Mayu O and Parveen, Salina and Blachere, Nathalie E and Hale, Caryn and Zhang, Fan and Raychaudhuri, Soumya and Troyanskaya, Olga G and Darnell, Robert B} } @article {774, title = {TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 01}, pages = {182-195}, abstract = {

Congenital scoliosis (CS) is a birth defect with variable clinical and anatomical manifestations due to spinal malformation. The genetic etiology underlying about 10\% of CS cases in the Chinese population is compound inheritance by which the gene dosage is reduced below that of haploinsufficiency. In this genetic model, the trait manifests as a result of the combined effect of a rare variant and common pathogenic variant allele at a locus. From exome sequencing (ES) data of 523 patients in Asia and two patients in Texas, we identified six TBX6 gene-disruptive variants from 11 unrelated CS patients via ES and in vitro functional testing. The in trans mild hypomorphic allele was identified in 10 of the 11 subjects; as anticipated these 10 shared a similar spinal deformity of hemivertebrae. The remaining case has a homozygous variant in TBX6 (c.418C>T) and presents a more severe spinal deformity phenotype. We found decreased transcriptional activity and abnormal cellular localization as the molecular mechanisms for TBX6 missense loss-of-function alleles. Expanding the mutational spectrum of TBX6 pathogenic alleles enabled an increased molecular diagnostic detection rate, provided further evidence for the gene dosage-dependent genetic model underlying CS, and refined clinical classification.

}, keywords = {Alleles, Cell Line, Female, Gene Expression, Genes, Reporter, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Inheritance Patterns, Male, Models, Molecular, Molecular Diagnostic Techniques, Mutation, Missense, Phenotype, Protein Conformation, Radiography, Sequence Analysis, DNA, Spine, Structure-Activity Relationship, T-Box Domain Proteins, Whole Exome Sequencing}, issn = {1098-1004}, doi = {10.1002/humu.23907}, author = {Chen, Weisheng and Lin, Jiachen and Wang, Lianlei and Li, Xiaoxin and Zhao, Sen and Liu, Jiaqi and Akdemir, Zeynep C and Zhao, Yanxue and Du, Renqian and Ye, Yongyu and Song, Xiaofei and Zhang, Yuanqiang and Yan, Zihui and Yang, Xinzhuang and Lin, Mao and Shen, Jianxiong and Wang, Shengru and Gao, Na and Yang, Ying and Liu, Ying and Li, Wenli and Liu, Jia and Zhang, Na and Yang, Xu and Xu, Yuan and Zhang, Jianguo and Delgado, Mauricio R and Posey, Jennifer E and Qiu, Guixing and Rios, Jonathan J and Liu, Pengfei and Wise, Carol A and Zhang, Feng and Wu, Zhihong and Lupski, James R and Wu, Nan} } @article {662, title = {Identification and association of recurrent ALOXE3 mutation with non-bullous congenital ichthyosiform erythroderma in two ethnically distinct Pakistani families.}, journal = {Congenit Anom (Kyoto)}, volume = {59}, year = {2019}, month = {2019 May}, pages = {93-98}, abstract = {

Non-bullous congenital ichthyosiform erythroderma (NCIE) is characterized by skin scaling with erythema. In this study, two Pakistani families with NCIE are genetically characterized through Whole Exome and Sanger sequencing to identify molecular basis of the disease. We identified a nonsense homozygous c.2026C>T mutation of ALOXE3, causing premature termination of the eLOX3 protein (p.Q676X). In silico studies predicted impaired enzymatic activity of the premature truncated eLOX3, leading to abnormal synthesis of specific hepoxilin derivatives, essential for epidermal barrier formation. It is the first ever study reporting homozygotes of p.Q676X mutation in ethnically distinct two Pakistani families; otherwise, heterozygotes of the said mutation have been reported in South Asian population only. Hence, mutation seems to be region-specific and may be useful for molecular diagnosis of NCIE. Moreover, our findings should help in genetic counseling and career screening.

}, keywords = {8,11,14-Eicosatrienoic Acid, Adolescent, Adult, Base Sequence, Case-Control Studies, Child, Child, Preschool, Codon, Nonsense, Ethnic Groups, Female, Flavanones, Gene Expression, Homozygote, Humans, Ichthyosis, Lamellar, Lipoxygenase, Male, Middle Aged, Molecular Docking Simulation, Pakistan, Pedigree, Protein Binding, Protein Structure, Secondary, Skin, Whole Exome Sequencing}, issn = {1741-4520}, doi = {10.1111/cga.12303}, author = {Rahman, Simeen Ber and Mir, Asif and Ahmad, Nafees and Haider, Syed Husnain and Malik, Salman Akbar and Nasir, Muhammad} } @article {571, title = {Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 02 15}, pages = {797}, abstract = {

FXR1 is an alternatively spliced gene that encodes RNA binding proteins (FXR1P) involved in muscle development. In contrast to other tissues, cardiac and skeletal muscle express two FXR1P isoforms that incorporate an additional exon-15. We report that recessive mutations in this particular exon of FXR1 cause congenital multi-minicore myopathy in humans and mice. Additionally, we show that while Myf5-dependent depletion of all FXR1P isoforms is neonatal lethal, mice carrying mutations in exon-15 display non-lethal myopathies which vary in severity depending on the specific effect of each mutation on the protein.

}, keywords = {Animals, Cells, Cultured, Exons, Gene Expression, Genes, Recessive, Genetic Predisposition to Disease, HEK293 Cells, HeLa Cells, Humans, Mice, Transgenic, Muscle, Skeletal, Mutation, Myopathies, Structural, Congenital, Ophthalmoplegia, RNA-Binding Proteins, Ryanodine Receptor Calcium Release Channel}, issn = {2041-1723}, doi = {10.1038/s41467-019-08548-9}, author = {Esta{\~n}, Mar{\'\i}a Cristina and Fern{\'a}ndez-N{\'u}{\~n}ez, Elisa and Zaki, Maha S and Esteban, Mar{\'\i}a Isabel and Donkervoort, Sandra and Hawkins, Cynthia and Caparros-Martin, Jos{\'e} A and Saade, Dimah and Hu, Ying and Bolduc, Veronique and Chao, Katherine Ru-Yui and Nevado, Juli{\'a}n and Lamuedra, Ana and Largo, Raquel and Herrero-Beaumont, Gabriel and Regadera, Javier and Hernandez-Chico, Concepci{\'o}n and Tizzano, Eduardo F and Martinez-Glez, Victor and Carvajal, Jaime J and Zong, Ruiting and Nelson, David L and Otaify, Ghada A and Temtamy, Samia and Aglan, Mona and Issa, Mahmoud and B{\"o}nnemann, Carsten G and Lapunzina, Pablo and Yoon, Grace and Ruiz-Perez, Victor L} } @article {371, title = {Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency.}, journal = {Mitochondrion}, volume = {34}, year = {2017}, month = {2017 05}, pages = {84-90}, abstract = {

We report the clinical, biochemical, and molecular findings in two brothers with encephalopathy and multi-systemic disease. Abnormal transferrin glycoforms were suggestive of a type I congenital disorder of glycosylation (CDG). While exome sequencing was negative for CDG related candidate genes, the testing revealed compound heterozygous mutations in the mitochondrial elongation factor G gene (GFM1). One of the mutations had been reported previously while the second, novel variant was found deep in intron 6, activating a cryptic splice site. Functional studies demonstrated decreased GFM1 protein levels, suggested disrupted assembly of mitochondrial complexes III and V and decreased activities of mitochondrial complexes I and IV, all indicating combined OXPHOS deficiency.

}, keywords = {Child, Child, Preschool, Congenital Abnormalities, Gene Expression, Humans, Infant, Infant, Newborn, Male, Mitochondrial Proteins, Oxidative Phosphorylation, Peptide Elongation Factor G, RNA Splice Sites}, issn = {1872-8278}, doi = {10.1016/j.mito.2017.02.004}, author = {Simon, Mariella T and Ng, Bobby G and Friederich, Marisa W and Wang, Raymond Y and Boyer, Monica and Kircher, Martin and Collard, Renata and Buckingham, Kati J and Chang, Richard and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J and Van Hove, Johan L K and Freeze, Hudson H and Abdenur, Jose E} } @article {426, title = {Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Nov}, pages = {1593-1601}, abstract = {

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8\%, including a recessive founder mutation in GDF1 accounting for \~{}5\% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for \~{}11\% of Shone complex, and dominant FLT4 mutations accounting for 2.3\% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8\% of cases, including \~{}3\% of isolated CHD patients and \~{}28\% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70\% probability of being disease related. DNMs in \~{}440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

}, keywords = {Adult, Autistic Disorder, Cardiac Myosins, Case-Control Studies, Child, Exome, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Growth Differentiation Factor 1, Heart Defects, Congenital, Heterozygote, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Mutation, Myosin Heavy Chains, Pedigree, Risk, Vascular Endothelial Growth Factor Receptor-3}, issn = {1546-1718}, doi = {10.1038/ng.3970}, author = {Jin, Sheng Chih and Homsy, Jason and Zaidi, Samir and Lu, Qiongshi and Morton, Sarah and DePalma, Steven R and Zeng, Xue and Qi, Hongjian and Chang, Weni and Sierant, Michael C and Hung, Wei-Chien and Haider, Shozeb and Zhang, Junhui and Knight, James and Bjornson, Robert D and Castaldi, Christopher and Tikhonoa, Irina R and Bilguvar, Kaya and Mane, Shrikant M and Sanders, Stephan J and Mital, Seema and Russell, Mark W and Gaynor, J William and Deanfield, John and Giardini, Alessandro and Porter, George A and Srivastava, Deepak and Lo, Cecelia W and Shen, Yufeng and Watkins, W Scott and Yandell, Mark and Yost, H Joseph and Tristani-Firouzi, Martin and Newburger, Jane W and Roberts, Amy E and Kim, Richard and Zhao, Hongyu and Kaltman, Jonathan R and Goldmuntz, Elizabeth and Chung, Wendy K and Seidman, Jonathan G and Gelb, Bruce D and Seidman, Christine E and Lifton, Richard P and Brueckner, Martina} } @article {638, title = {A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome.}, journal = {Nat Commun}, volume = {8}, year = {2017}, month = {2017 07 06}, pages = {16077}, abstract = {

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymk zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.

}, keywords = {Adult, Amino Acid Sequence, Animals, Cell Fusion, Child, Disease Models, Animal, Embryo, Nonmammalian, Female, Gene Expression, Genes, Recessive, Genetic Complementation Test, Humans, Infant, Male, Membrane Proteins, Mobius Syndrome, Morphogenesis, Muscle Proteins, Muscle, Skeletal, Muscular Diseases, Mutation, Myoblasts, Pedigree, Pierre Robin Syndrome, Sequence Alignment, Sequence Homology, Amino Acid, Zebrafish, Zebrafish Proteins}, issn = {2041-1723}, doi = {10.1038/ncomms16077}, author = {Di Gioia, Silvio Alessandro and Connors, Samantha and Matsunami, Norisada and Cannavino, Jessica and Rose, Matthew F and Gilette, Nicole M and Artoni, Pietro and de Macena Sobreira, Nara Lygia and Chan, Wai-Man and Webb, Bryn D and Robson, Caroline D and Cheng, Long and Van Ryzin, Carol and Ramirez-Martinez, Andres and Mohassel, Payam and Leppert, Mark and Scholand, Mary Beth and Grunseich, Christopher and Ferreira, Carlos R and Hartman, Tyler and Hayes, Ian M and Morgan, Tim and Markie, David M and Fagiolini, Michela and Swift, Amy and Chines, Peter S and Speck-Martins, Carlos E and Collins, Francis S and Jabs, Ethylin Wang and B{\"o}nnemann, Carsten G and Olson, Eric N and Carey, John C and Robertson, Stephen P and Manoli, Irini and Engle, Elizabeth C} } @article {537, title = {Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly.}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 03 08}, pages = {43708}, abstract = {

Recessive mutations in WD repeat domain 62 (WDR62) cause microcephaly and a wide spectrum of severe brain malformations. Disruption of the mouse ortholog results in microcephaly underlain by reduced proliferation of neocortical progenitors during late neurogenesis, abnormalities in asymmetric centrosome inheritance leading to neuronal migration delays, and altered neuronal differentiation. Spindle pole localization of WDR62 and mitotic progression are defective in patient-derived fibroblasts, which, similar to mouse neocortical progenitors, transiently arrest at prometaphase. Expression of WDR62 is closely correlated with components of the chromosome passenger complex (CPC), a key regulator of mitosis. Wild type WDR62, but not disease-associated mutant forms, interacts with the CPC core enzyme Aurora kinase B and staining of CPC components at centromeres is altered in patient-derived fibroblasts. Our findings demonstrate critical and diverse functions of WDR62 in neocortical development and provide insight into the mechanisms by which its disruption leads to a plethora of structural abnormalities.

}, keywords = {Animals, Aurora Kinase B, Brain, Cell Cycle, Cell Differentiation, Cell Proliferation, Centrosome, Consanguinity, Disease Models, Animal, Epistasis, Genetic, Fluorescent Antibody Technique, Gene Expression, Humans, Inheritance Patterns, Male, Mice, Mice, Knockout, Microcephaly, Mutation, Nerve Tissue Proteins, Neural Stem Cells, Pedigree, Whole Genome Sequencing}, issn = {2045-2322}, doi = {10.1038/srep43708}, author = {Sgourdou, Paraskevi and Mishra-Gorur, Ketu and Saotome, Ichiko and Henagariu, Octavian and Tuysuz, Beyhan and Campos, Cynthia and Ishigame, Keiko and Giannikou, Krinio and Quon, Jennifer L and {\v S}estan, Nenad and {\c C}a{\u g}layan, Ahmet O and G{\"u}nel, Murat and Louvi, Angeliki} } @article {86, title = {FOXE3 mutations predispose to thoracic aortic aneurysms and dissections.}, journal = {J Clin Invest}, volume = {126}, year = {2016}, month = {2016 Mar 01}, pages = {948-61}, abstract = {

The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3-/- mice with p53-/- mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.

}, keywords = {Adult, Aneurysm, Dissecting, Animals, Aorta, Aortic Aneurysm, Thoracic, Apoptosis, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, Female, Forkhead Transcription Factors, Gene Expression, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Muscle, Smooth, Vascular, Mutation, Missense, Myocytes, Smooth Muscle, Pedigree, Tumor Suppressor Protein p53, Vascular Remodeling, Zebrafish}, issn = {1558-8238}, doi = {10.1172/JCI83778}, author = {Kuang, Shao-Qing and Medina-Martinez, Olga and Guo, Dong-Chuan and Gong, Limin and Regalado, Ellen S and Reynolds, Corey L and Boileau, Catherine and Jondeau, Guillaume and Prakash, Siddharth K and Kwartler, Callie S and Zhu, Lawrence Yang and Peters, Andrew M and Duan, Xue-Yan and Bamshad, Michael J and Shendure, Jay and Nickerson, Debbie A and Santos-Cortez, Regie L and Dong, Xiurong and Leal, Suzanne M and Majesky, Mark W and Swindell, Eric C and Jamrich, Milan and Milewicz, Dianna M} } @article {96, title = {A patient with a novel homozygous missense mutation in FTO and concomitant nonsense mutation in CETP.}, journal = {J Hum Genet}, volume = {61}, year = {2016}, month = {2016 May}, pages = {395-403}, abstract = {

The fat mass and obesity associated (FTO) gene has previously been associated with a variety of diseases and conditions, notably obesity, acute coronary syndrome and metabolic syndrome. Reports describing mutations in FTO as well as in FTO animal models have further demonstrated a role for FTO in the development of the brain and other organs. Here, we describe a patient born of consanguineous union who presented with microcephaly, developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia and other various phenotypic abnormalities. Whole-exome sequencing revealed a novel homozygous missense mutation in FTO and a nonsense mutation in the cholesteryl ester transfer protein (CETP). Exome copy number variation analysis revealed no disease-causing large duplications or deletions within coding regions. Patient{\textquoteright}s, her parents{\textquoteright} and non-related control{\textquoteright} fibroblasts were analyzed for morphologic defects, abnormal proliferation, apoptosis and transcriptome profile. We have shown that FTO is located in the nucleus of cells from each tested sample. Western blot analysis demonstrated no changes in patient FTO. Quantitative (qPCR) analysis revealed slightly decreased levels of FTO expression in patient cells compared with controls. No morphological or proliferation differences between the patient and control fibroblasts were observed. There is still much to be learned about the molecular mechanisms by which mutations in FTO contribute to such severe phenotypes.

}, keywords = {Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Apoptosis, Biopsy, Child, Preschool, Cholesterol Ester Transfer Proteins, Computational Biology, Consanguinity, DNA Copy Number Variations, DNA Mutational Analysis, Exome, Female, Gene Expression, Gene Expression Profiling, Genetic Association Studies, Genotype, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Mutation, Missense, Phenotype, Transcriptome}, issn = {1435-232X}, doi = {10.1038/jhg.2015.160}, author = {{\c C}a{\u g}layan, Ahmet O and Tuysuz, Beyhan and Co{\c s}kun, S{\"u}leyman and Quon, Jennifer and Harmanc{\i}, Akdes S and Baranoski, Jacob F and Baran, Bur{\c c}in and Erson-Omay, E Zeynep and Henegariu, Octavian and Mane, Shrikant M and Bilguvar, Kaya and Yasuno, Katsuhito and G{\"u}nel, Murat} } @article {63, title = {PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive.}, journal = {Ann Neurol}, volume = {80}, year = {2016}, month = {2016 07}, pages = {59-70}, abstract = {

OBJECTIVE: A study was undertaken to characterize the clinical features of the newly described hypomyelinating leukodystrophy type 10 with microcephaly. This is an autosomal recessive disorder mapped to chromosome 1q42.12 due to mutations in the PYCR2 gene, encoding an enzyme involved in proline synthesis in mitochondria.

METHODS: From several international clinics, 11 consanguineous families were identified with PYCR2 mutations by whole exome or targeted sequencing, with detailed clinical and radiological phenotyping. Selective mutations from patients were tested for effect on protein function.

RESULTS: The characteristic clinical presentation of patients with PYCR2 mutations included failure to thrive, microcephaly, craniofacial dysmorphism, progressive psychomotor disability, hyperkinetic movements, and axial hypotonia with variable appendicular spasticity. Patients did not survive beyond the first decade of life. Brain magnetic resonance imaging showed global brain atrophy and white matter T2 hyperintensities. Routine serum metabolic profiles were unremarkable. Both nonsense and missense mutations were identified, which impaired protein multimerization.

INTERPRETATION: PYCR2-related syndrome represents a clinically recognizable condition in which PYCR2 mutations lead to protein dysfunction, not detectable on routine biochemical assessments. Mutations predict a poor outcome, probably as a result of impaired mitochondrial function. Ann Neurol 2016;80:59-70.

}, keywords = {Adolescent, Child, Child, Preschool, Codon, Nonsense, Exome, Failure to Thrive, Female, Fibroblasts, Gene Expression, Genetic Predisposition to Disease, Genotype, Humans, Infant, Male, Microcephaly, Mutation, Missense, Phenotype, Primary Cell Culture, Pyrroline Carboxylate Reductases, Syndrome, Transfection, Young Adult}, issn = {1531-8249}, doi = {10.1002/ana.24678}, author = {Zaki, Maha S and Bhat, Gifty and Sultan, Tipu and Issa, Mahmoud and Jung, Hea-Jin and Dikoglu, Esra and Selim, Laila and G Mahmoud, Imam and Abdel-Hamid, Mohamed S and Abdel-Salam, Ghada and Marin-Valencia, Isaac and Gleeson, Joseph G} } @article {108, title = {De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Dec 03}, pages = {904-13}, abstract = {

Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5{\textquoteright} end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(*)) and c.35_38delTCAA (p.Ile12Lysfs(*)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5{\textquoteright} end of the geminin protein. All three GMNN mutations identified alter sites 5{\textquoteright} to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.

}, keywords = {Adolescent, Amino Acid Sequence, Base Sequence, Cell Cycle, Child, Preschool, Congenital Microtia, Dwarfism, Exons, Female, Geminin, Gene Expression, Genes, Dominant, Growth Disorders, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Inheritance Patterns, Male, Micrognathism, Molecular Sequence Data, Mutation, Patella, Pedigree, Protein Stability, Proteolysis, RNA Splicing, Sequence Alignment}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.11.006}, author = {Burrage, Lindsay C and Charng, Wu-Lin and Eldomery, Mohammad K and Willer, Jason R and Davis, Erica E and Lugtenberg, Dorien and Zhu, Wenmiao and Leduc, Magalie S and Akdemir, Zeynep C and Azamian, Mahshid and Zapata, Gladys and Hernandez, Patricia P and Schoots, Jeroen and de Munnik, Sonja A and Roepman, Ronald and Pearring, Jillian N and Jhangiani, Shalini and Katsanis, Nicholas and Vissers, Lisenka E L M and Brunner, Han G and Beaudet, Arthur L and Rosenfeld, Jill A and Muzny, Donna M and Gibbs, Richard A and Eng, Christine M and Xia, Fan and Lalani, Seema R and Lupski, James R and Bongers, Ernie M H F and Yang, Yaping} } @article {171, title = {Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism.}, journal = {Elife}, volume = {4}, year = {2015}, month = {2015 Apr 24}, pages = {e06315}, abstract = {

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5\%) shared the identical, previously unidentified, heterozygous CACNA1H(M1549V) mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1H(M1549V) showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca(2+), the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.

}, keywords = {Adolescent, Adult, Age of Onset, Aldosterone, Amino Acid Sequence, Calcium, Calcium Channels, T-Type, Calcium Signaling, Child, Child, Preschool, Female, Gene Expression, Genotype, Heterozygote, Humans, Hyperaldosteronism, Hypertension, Infant, Male, Membrane Potentials, Middle Aged, Molecular Sequence Data, Mutation, Phenotype, Recurrence, Sequence Alignment, Zona Glomerulosa}, issn = {2050-084X}, doi = {10.7554/eLife.06315}, author = {Scholl, Ute I and St{\"o}lting, Gabriel and Nelson-Williams, Carol and Vichot, Alfred A and Choi, Murim and Loring, Erin and Prasad, Manju L and Goh, Gerald and Carling, Tobias and Juhlin, C Christofer and Quack, Ivo and Rump, Lars C and Thiel, Anne and Lande, Marc and Frazier, Britney G and Rasoulpour, Majid and Bowlin, David L and Sethna, Christine B and Trachtman, Howard and Fahlke, Christoph and Lifton, Richard P} } @article {162, title = {A second locus for Schneckenbecken dysplasia identified by a mutation in the gene encoding inositol polyphosphate phosphatase-like 1 (INPPL1).}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Oct}, pages = {2470-3}, keywords = {Exome, Gene Expression, Genetic Loci, Gestational Age, Homozygote, Humans, Hydrops Fetalis, Infant, Newborn, Male, Mutation, Osteochondrodysplasias, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases, Stillbirth}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37173}, author = {Lee, Hane and Nevarez, Lisette and Lachman, Ralph S and Wilcox, William R and Krakow, Deborah and Cohn, Daniel H} } @article {285, title = {Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D.}, journal = {Genet Med}, volume = {16}, year = {2014}, month = {2014 May}, pages = {386-394}, abstract = {

PURPOSE: Copy-number variations as a mutational mechanism contribute significantly to human disease. Approximately one-half of the patients with Charcot-Marie-Tooth (CMT) disease have a 1.4 Mb duplication copy-number variation as the cause of their neuropathy. However, non-CMT1A neuropathy patients rarely have causative copy-number variations, and to date, autosomal-recessive disease has not been associated with copy-number variation as a mutational mechanism.

METHODS: We performed Agilent 8 {\texttimes} 60 K array comparative genomic hybridization on DNA from 12 recessive Turkish families with CMT disease. Additional molecular studies were conducted to detect breakpoint junctions and to evaluate gene expression levels in a family in which we detected an intragenic duplication copy-number variation.

RESULTS: We detected an ~6.25 kb homozygous intragenic duplication in NDRG1, a gene known to be causative for recessive HMSNL/CMT4D, in three individuals from a Turkish family with CMT neuropathy. Further studies showed that this intragenic copy-number variation resulted in a homozygous duplication of exons 6-8 that caused decreased mRNA expression of NDRG1.

CONCLUSION: Exon-focused high-resolution array comparative genomic hybridization enables the detection of copy-number variation carrier states in recessive genes, particularly small copy-number variations encompassing or disrupting single genes. In families for whom a molecular diagnosis has not been elucidated by conventional clinical assays, an assessment for copy-number variations in known CMT genes might be considered.

}, keywords = {Adult, Base Sequence, Cell Cycle Proteins, Charcot-Marie-Tooth Disease, Comparative Genomic Hybridization, DNA Copy Number Variations, Female, Gene Duplication, Gene Expression, Genes, Recessive, Humans, Intracellular Signaling Peptides and Proteins, Male, Mutation, Refsum Disease, Sequence Analysis, DNA, Turkey, Young Adult}, issn = {1530-0366}, doi = {10.1038/gim.2013.155}, author = {Okamoto, Yuji and Goksungur, Meryem Tuba and Pehlivan, Davut and Beck, Christine R and Gonzaga-Jauregui, Claudia and Muzny, Donna M and Atik, Mehmed M and Carvalho, Claudia M B and Matur, Zeliha and Bayraktar, Serife and Boone, Philip M and Akyuz, Kaya and Gibbs, Richard A and Battaloglu, Esra and Parman, Yesim and Lupski, James R} } @article {243, title = {Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jun 05}, pages = {915-23}, abstract = {

We identified four different missense mutations in the single-exon gene MAB21L2 in eight individuals with bilateral eye malformations from five unrelated families via three independent exome sequencing projects. Three mutational events altered the same amino acid (Arg51), and two were identical de novo mutations (c.151C>T [p.Arg51Cys]) in unrelated children with bilateral anophthalmia, intellectual disability, and rhizomelic skeletal dysplasia. c.152G>A (p.Arg51His) segregated with autosomal-dominant bilateral colobomatous microphthalmia in a large multiplex family. The fourth heterozygous mutation (c.145G>A [p.Glu49Lys]) affected an amino acid within two residues of Arg51 in an adult male with bilateral colobomata. In a fifth family, a homozygous mutation (c.740G>A [p.Arg247Gln]) altering a different region of the protein was identified in two male siblings with bilateral retinal colobomata. In mouse embryos, Mab21l2 showed strong expression in the developing eye, pharyngeal arches, and limb bud. As predicted by structural homology, wild-type MAB21L2 bound single-stranded RNA, whereas this activity was lost in all altered forms of the protein. MAB21L2 had no detectable nucleotidyltransferase activity in~vitro, and its function remains unknown. Induced expression of wild-type MAB21L2 in human embryonic kidney 293 cells increased phospho-ERK (pERK1/2) signaling. Compared to the wild-type and p.Arg247Gln proteins, the proteins with the Glu49 and Arg51 variants had increased stability. Abnormal persistence of pERK1/2 signaling in MAB21L2-expressing cells during development is a plausible pathogenic mechanism for the heterozygous mutations. The phenotype associated with the homozygous mutation might be a consequence of complete loss of MAB21L2 RNA binding, although the cellular function of this interaction remains unknown.

}, keywords = {Adult, Alleles, Animals, Anophthalmos, Brain Diseases, Metabolic, Inborn, Coloboma, Corneal Opacity, Exome, Eye Proteins, Female, Gene Expression, HEK293 Cells, Heterozygote, Homozygote, Humans, Intellectual Disability, Intracellular Signaling Peptides and Proteins, Male, Mice, Microcephaly, Microphthalmos, Mutation, Missense, Pedigree, Phenotype, Protein Conformation, Signal Transduction}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.05.005}, author = {Rainger, Joe and Pehlivan, Davut and Johansson, Stefan and Bengani, Hemant and Sanchez-Pulido, Luis and Williamson, Kathleen A and Ture, Mehmet and Barker, Heather and Rosendahl, Karen and Spranger, J{\"u}rgen and Horn, Denise and Meynert, Alison and Floyd, James A B and Prescott, Trine and Anderson, Carl A and Rainger, Jacqueline K and Karaca, Ender and Gonzaga-Jauregui, Claudia and Jhangiani, Shalini and Muzny, Donna M and Seawright, Anne and Soares, Dinesh C and Kharbanda, Mira and Murday, Victoria and Finch, Andrew and Gibbs, Richard A and van Heyningen, Veronica and Taylor, Martin S and Yakut, Tahsin and Knappskog, Per M and Hurles, Matthew E and Ponting, Chris P and Lupski, James R and Houge, Gunnar and FitzPatrick, David R} }