@article {919, title = {DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 12 03}, pages = {1113-1128}, abstract = {

The discovery of >60 monogenic causes of nephrotic syndrome (NS) has revealed a central role for the actin regulators RhoA/Rac1/Cdc42 and their effectors, including the formin INF2. By whole-exome sequencing (WES), we here discovered bi-allelic variants in the formin DAAM2 in four unrelated families with steroid-resistant NS. We show that DAAM2 localizes to the cytoplasm in podocytes and in kidney sections. Further, the variants impair DAAM2-dependent actin remodeling processes: wild-type DAAM2 cDNA, but not cDNA representing missense variants found in individuals with NS, rescued reduced podocyte migration rate (PMR) and restored reduced filopodia formation in shRNA-induced DAAM2-knockdown podocytes. Filopodia restoration was also induced by the formin-activating molecule IMM-01. DAAM2 also co-localizes and co-immunoprecipitates with INF2, which is intriguing since variants in both formins cause NS. Using in~vitro bulk and TIRF microscopy assays, we find that DAAM2 variants alter actin assembly activities of the formin. In a Xenopus daam2-CRISPR knockout model, we demonstrate actin dysregulation in~vivo and glomerular maldevelopment that is rescued by WT-DAAM2 mRNA. We conclude that DAAM2 variants are a likely cause of monogenic human SRNS due to actin dysregulation in podocytes. Further, we provide evidence that DAAM2-associated SRNS may be amenable to treatment using actin regulating compounds.

}, keywords = {Actins, Alleles, Animals, Animals, Genetically Modified, Cell Movement, Cytoplasm, Formins, Genetic Variation, Humans, Kidney, Kidney Glomerulus, Microfilament Proteins, Mutation, Missense, Nephrotic Syndrome, Podocytes, Pseudopodia, rho GTP-Binding Proteins, RNA, Small Interfering, Whole Exome Sequencing, Xenopus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.11.008}, author = {Schneider, Ronen and Deutsch, Konstantin and Hoeprich, Gregory J and Marquez, Jonathan and Hermle, Tobias and Braun, Daniela A and Seltzsam, Steve and Kitzler, Thomas M and Mao, Youying and Buerger, Florian and Majmundar, Amar J and Onuchic-Whitford, Ana C and Kolvenbach, Caroline M and Schierbaum, Luca and Schneider, Sophia and Halawi, Abdul A and Nakayama, Makiko and Mann, Nina and Connaughton, Dervla M and Kl{\"a}mbt, Verena and Wagner, Matias and Riedhammer, Korbinian M and Renders, Lutz and Katsura, Yoshichika and Thumkeo, Dean and Soliman, Neveen A and Mane, Shrikant and Lifton, Richard P and Shril, Shirlee and Khokha, Mustafa K and Hoefele, Julia and Goode, Bruce L and Hildebrandt, Friedhelm} } @article {583, title = {Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {229-245}, abstract = {

Primary ciliary dyskinesia (PCD) is a genetic disorder in which impaired ciliary function leads to chronic airway disease. Exome sequencing of a PCD subject identified an apparent homozygous frameshift variant, c.887_890delTAAG (p.Val296Glyfs13), in exon 5; this frameshift introduces a stop codon in amino acid 308 of the growth arrest-specific protein 2-like 2 (GAS2L2). Further genetic screening of unrelated PCD subjects identified a second proband with a compound heterozygous variant carrying the identical frameshift variant and a large deletion (c.867_343+1207del; p.?) starting in exon 5. Both individuals had clinical features of PCD but normal ciliary axoneme structure. In this research, using human nasal cells, mouse models, and X.laevis embryos, we show that GAS2L2 is abundant at the apical surface of ciliated cells, where it localizes with basal bodies, basal feet, rootlets, and actin filaments. Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8~Hz versus control = 15.8~Hz) ciliary-beat pattern. These results were recapitulated in Gas2l2 mouse tracheal epithelial cell (mTEC) cultures and in X.~laevis embryos treated with Gas2l2 morpholinos. In mice, the absence of Gas2l2 caused neonatal death, and the conditional deletion of Gas2l2 impaired mucociliary clearance (MCC) and led to mucus accumulation. These results show that a pathogenic variant in GAS2L2 causes a genetic defect in ciliary orientation and impairs MCC and results in~PCD.

}, keywords = {Animals, Cilia, Ciliary Motility Disorders, Disease Models, Animal, Exons, Female, Gene Deletion, Genes, Lethal, Humans, Male, Mice, Mice, Knockout, Microfilament Proteins, Microtubule-Associated Proteins, Phenotype, Rotation, Xenopus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.009}, author = {Bustamante-Marin, Ximena M and Yin, Wei-Ning and Sears, Patrick R and Werner, Michael E and Brotslaw, Eva J and Mitchell, Brian J and Jania, Corey M and Zeman, Kirby L and Rogers, Troy D and Herring, Laura E and Refab{\'e}rt, Luc and Thomas, Lucie and Amselem, Serge and Escudier, Estelle and Legendre, Marie and Grubb, Barbara R and Knowles, Michael R and Zariwala, Maimoona A and Ostrowski, Lawrence E} } @article {457, title = {Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 12 01}, pages = {4257-4269}, abstract = {

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of chronic kidney disease. Here, we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS. While all AVIL mutations resulted in a marked loss of its actin-bundling ability, truncation of AVIL also disrupted colocalization with F-actin, thereby leading to impaired actin binding and severing. Additionally, AVIL colocalized and interacted with the phospholipase enzyme PLCE1 and with the ARP2/3 actin-modulating complex. Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR). These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants. The PMR was increased by overexpression of WT Avil or PLCE1, or by EGF stimulation; however, this increased PMR was ameliorated by inhibition of the ARP2/3 complex, indicating that ARP-dependent lamellipodia formation occurs downstream of AVIL and PLCE1 function. Together, these results delineate a comprehensive pathogenic axis of SRNS that integrates loss of AVIL function with alterations in the action of PLCE1, an established SRNS protein.

}, keywords = {Actin-Related Protein 2-3 Complex, Cell Movement, Diglycerides, Female, Humans, Male, Microfilament Proteins, Mutation, Nephrotic Syndrome, Phosphoinositide Phospholipase C, Podocytes, Pseudopodia}, issn = {1558-8238}, doi = {10.1172/JCI94138}, author = {Rao, Jia and Ashraf, Shazia and Tan, Weizhen and van der Ven, Amelie T and Gee, Heon Yung and Braun, Daniela A and Feh{\'e}r, Krisztina and George, Sudeep P and Esmaeilniakooshkghazi, Amin and Choi, Won-Il and Jobst-Schwan, Tilman and Schneider, Ronen and Schmidt, Johanna Magdalena and Widmeier, Eugen and Warejko, Jillian K and Hermle, Tobias and Schapiro, David and Lovric, Svjetlana and Shril, Shirlee and Daga, Ankana and Nayir, Ahmet and Shenoy, Mohan and Tse, Yincent and Bald, Martin and Helmchen, Udo and Mir, Sevgi and Berdeli, Afig and Kari, Jameela A and El Desoky, Sherif and Soliman, Neveen A and Bagga, Arvind and Mane, Shrikant and Jairajpuri, Mohamad A and Lifton, Richard P and Khurana, Seema and Martins, Jose C and Hildebrandt, Friedhelm} } @article {437, title = {Asprosin is a centrally acting orexigenic hormone.}, journal = {Nat Med}, volume = {23}, year = {2017}, month = {2017 Dec}, pages = {1444-1453}, abstract = {

Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood-brain barrier and directly activates orexigenic AgRP neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.

}, keywords = {Adolescent, Adult, Animals, Appetite Depressants, Appetite Regulation, Female, Humans, Hypothalamus, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Neurons, Peptide Fragments, Peptide Hormones, Rats, Signal Transduction, Young Adult}, issn = {1546-170X}, doi = {10.1038/nm.4432}, author = {Duerrschmid, Clemens and He, Yanlin and Wang, Chunmei and Li, Chia and Bournat, Juan C and Romere, Chase and Saha, Pradip K and Lee, Mark E and Phillips, Kevin J and Jain, Mahim and Jia, Peilin and Zhao, Zhongming and Farias, Monica and Wu, Qi and Milewicz, Dianna M and Sutton, V Reid and Moore, David D and Butte, Nancy F and Krashes, Michael J and Xu, Yong and Chopra, Atul R} } @article {66, title = {Asprosin, a Fasting-Induced Glucogenic Protein Hormone.}, journal = {Cell}, volume = {165}, year = {2016}, month = {2016 Apr 21}, pages = {566-79}, abstract = {

Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means~has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome.

}, keywords = {Adipose Tissue, White, Amino Acid Sequence, Animals, Antibodies, Circadian Rhythm, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Fasting, Female, Fetal Growth Retardation, Glucose, Humans, Insulin, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Microfilament Proteins, Molecular Sequence Data, Peptide Fragments, Peptide Hormones, Progeria, Recombinant Proteins, Sequence Alignment}, issn = {1097-4172}, doi = {10.1016/j.cell.2016.02.063}, author = {Romere, Chase and Duerrschmid, Clemens and Bournat, Juan and Constable, Petra and Jain, Mahim and Xia, Fan and Saha, Pradip K and Del Solar, Maria and Zhu, Bokai and York, Brian and Sarkar, Poonam and Rendon, David A and Gaber, M Waleed and LeMaire, Scott A and Coselli, Joseph S and Milewicz, Dianna M and Sutton, V Reid and Butte, Nancy F and Moore, David D and Chopra, Atul R} } @article {188, title = {FBN1 contributing to familial congenital diaphragmatic hernia.}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Apr}, pages = {831-6}, abstract = {

Congenital diaphragmatic hernia (CDH) is a relatively common, life--threatening birth defect. We present a family with recurrent CDH--paraesophageal and central--for whom exome sequencing (ES) revealed a frameshift mutation (c.4969_4970insA, p.Ile1657Asnfs*30) in the fibrillin 1 gene (FBN1) that causes Marfan syndrome. A diagnosis of Marfan syndrome had not been considered previously in this family. However, a review of the literature demonstrated that FBN1 mutations have an unusual pattern of CDH in which paraesophageal hernias are particularly common. Subsequent clinical evaluations revealed evidence for ectopia lentis in affected family members supporting a clinical diagnosis of Marfan syndrome. Since only two other cases of familial CDH have been described in association with FBN1 mutations, we investigated an oligogenic hypothesis by examining ES data for deleterious sequence changes in other CDH-related genes. This search revealed putatively deleterious sequence changes in four other genes that have been shown to cause diaphragm defects in humans and/or mice--FREM1, DES, PAX3 and MET. It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. However, their individual contribution is likely to be small compared to that of the frameshift mutation in FBN1. We conclude that ES can be used to identify both major and minor genetic factors that may contribute to CDH. These results also suggest that ES should be considered in the diagnostic evaluation of individuals and families with CDH, particularly when other diagnostic modalities have failed to reveal a molecular etiology.

}, keywords = {Adult, Child, Preschool, DNA Mutational Analysis, Exome, Female, Fibrillin-1, Fibrillins, Frameshift Mutation, Genetic Association Studies, Hernias, Diaphragmatic, Congenital, Humans, Male, Marfan Syndrome, Microfilament Proteins, Pedigree}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36960}, author = {Beck, Tyler F and Campeau, Philippe M and Jhangiani, Shalini N and Gambin, Tomasz and Li, Alexander H and Abo-Zahrah, Reem and Jordan, Valerie K and Hernandez-Garcia, Andres and Wiszniewski, Wojciech K and Muzny, Donna and Gibbs, Richard A and Boerwinkle, Eric and Lupski, James R and Lee, Brendan and Reardon, Willie and Scott, Daryl A} } @article {205, title = {Biallelic truncating mutations in FMN2, encoding the actin-regulatory protein Formin 2, cause nonsyndromic autosomal-recessive intellectual disability.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Dec 04}, pages = {721-8}, abstract = {

Dendritic spines represent the major site of neuronal activity in the brain; they serve as the receiving point for neurotransmitters and undergo rapid activity-dependent morphological changes that correlate with learning and memory. Using a combination of homozygosity mapping and next-generation sequencing in two consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability, we identified truncating mutations in formin 2 (FMN2), encoding a protein that belongs to the formin family of actin cytoskeleton nucleation factors and is highly expressed in the maturing brain. We found that FMN2 localizes to punctae along dendrites and that germline inactivation of mouse Fmn2 resulted in animals with decreased spine density; such mice were previously demonstrated to have a conditioned fear-learning defect. Furthermore, patient neural cells derived from induced pluripotent stem cells showed correlated decreased synaptic density. Thus, FMN2 mutations link intellectual disability either directly or indirectly to the regulation of actin-mediated synaptic spine density.

}, keywords = {Adolescent, Adult, Base Sequence, Chromosome Disorders, Cohort Studies, Consanguinity, Egypt, Exome, Female, Genes, Recessive, Genetic Linkage, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Intellectual Disability, Male, Microfilament Proteins, Molecular Sequence Data, Nuclear Proteins, Pakistan, Pedigree, Sequence Analysis, DNA, Sequence Deletion}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.10.016}, author = {Law, Rosalind and Dixon-Salazar, Tracy and Jerber, Julie and Cai, Na and Abbasi, Ansar A and Zaki, Maha S and Mittal, Kirti and Gabriel, Stacey B and Rafiq, Muhammad Arshad and Khan, Valeed and Nguyen, Maria and Ali, Ghazanfar and Copeland, Brett and Scott, Eric and Vasli, Nasim and Mikhailov, Anna and Khan, Muhammad Nasim and Andrade, Danielle M and Ayaz, Muhammad and Ansar, Muhammad and Ayub, Muhammad and Vincent, John B and Gleeson, Joseph G} } @article {230, title = {Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy.}, journal = {J Clin Immunol}, volume = {34}, year = {2014}, month = {2014 Oct}, pages = {871-90}, abstract = {

PURPOSE: Coronin-1A deficiency is a recently recognized autosomal recessive primary immunodeficiency caused by mutations in CORO1A (OMIM 605000) that results in T-cell lymphopenia and is classified as T(-)B(+)NK(+)severe combined immunodeficiency (SCID). Only two other CORO1A-kindred are known to date, thus the defining characteristics are not well delineated. We identified a unique CORO1A-kindred.

METHODS: We captured a 10-year analysis of the immune-clinical phenotypes in two affected siblings from disease debut of age 7 years. Target-specific genetic studies were pursued but unrevealing. Telomere lengths were also assessed. Whole exome sequencing (WES) uncovered the molecular diagnosis and Western blot validated findings.

RESULTS: We found the compound heterozygous CORO1A variants: c.248_249delCT (p.P83RfsX10) and a novel mutation c.1077delC (p.Q360RfsX44) (NM_007074.3) in two affected non-consanguineous siblings that manifested as absent CD4CD45RA(+) (na{\"\i}ve) T and memory B cells, low NK cells and abnormally increased double-negative (DN) ϒδ T-cells. Distinguishing characteristics were late clinical debut with an unusual mucocutaneous syndrome of epidermodysplasia verruciformis-human papilloma virus (EV-HPV), molluscum contagiosum and oral-cutaneous herpetic ulcers; the older female sibling also had a disfiguring granulomatous tuberculoid leprosy. Both had bilateral bronchiectasis and the female died of EBV+ lymphomas at age 16 years. The younger surviving male, without malignancy, had reproducibly very short telomere lengths, not before appreciated in CORO1A mutations.

CONCLUSION: We reveal the third CORO1A-mutated kindred, with the immune phenotype of abnormal na{\"\i}ve CD4 and DN T-cells and newfound characteristics of a late/hypomorphic-like SCID of an EV-HPV mucocutaneous syndrome with also B and NK defects and shortened telomeres. Our findings contribute to the elucidation of the CORO1A-SCID-CID spectrum.

}, keywords = {Adolescent, B-Lymphocytes, CD4-Positive T-Lymphocytes, Child, DNA Mutational Analysis, Epidermodysplasia Verruciformis, Female, Genetic Predisposition to Disease, Granuloma, Heterozygote, Humans, Immunologic Memory, Killer Cells, Natural, Leprosy, Tuberculoid, Male, Microfilament Proteins, Molluscum Contagiosum, Mucous Membrane, Mutation, Papillomavirus Infections, Polymorphism, Genetic, Severe Combined Immunodeficiency, Siblings, Skin, Telomere Shortening}, issn = {1573-2592}, doi = {10.1007/s10875-014-0074-8}, author = {Stray-Pedersen, Asbjorg and Jouanguy, Emmanuelle and Crequer, Amandine and Bertuch, Alison A and Brown, Betty S and Jhangiani, Shalini N and Muzny, Donna M and Gambin, Tomasz and Sorte, Hanne and Sasa, Ghadir and Metry, Denise and Campbell, Judith and Sockrider, Marianna M and Dishop, Megan K and Scollard, David M and Gibbs, Richard A and Mace, Emily M and Orange, Jordan S and Lupski, James R and Casanova, Jean-Laurent and Noroski, Lenora M} } @article {324, title = {Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Jul 08}, pages = {922-7}, abstract = {

Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.

}, keywords = {Animals, Aortic Aneurysm, Thoracic, Disease Models, Animal, Female, Fibrillin-1, Fibrillins, Haploinsufficiency, Humans, Loeys-Dietz Syndrome, Male, Marfan Syndrome, Mice, Mice, Knockout, Mice, Mutant Strains, Microfilament Proteins, Mutation, Pedigree, Phenotype, Signal Transduction, Syndrome, Transforming Growth Factor beta2}, issn = {1546-1718}, doi = {10.1038/ng.2349}, author = {Lindsay, Mark E and Schepers, Dorien and Bolar, Nikhita Ajit and Doyle, Jefferson J and Gallo, Elena and Fert-Bober, Justyna and Kempers, Marlies J E and Fishman, Elliot K and Chen, Yichun and Myers, Loretha and Bjeda, Djahita and Oswald, Gretchen and Elias, Abdallah F and Levy, Howard P and Anderlid, Britt-Marie and Yang, Margaret H and Bongers, Ernie M H F and Timmermans, Janneke and Braverman, Alan C and Canham, Natalie and Mortier, Geert R and Brunner, Han G and Byers, Peter H and Van Eyk, Jennifer and Van Laer, Lut and Dietz, Harry C and Loeys, Bart L} }