WashU weekly Neuroscience publications

De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder
(2018) American Journal of Human Genetics, 103 (2), pp. 305-316.

Gregor, A.^a , Sadleir, L.G.^b , Asadollahi, R.^{c d} , Azzarello-Burri, S.^{c d} , Battaglia, A.^e , Ousager, L.B.^f , Boonsawat, P.^{c d} , Bruel, A.-L.^g , Buchert, R.^h , Calpena, E.ⁱ , Cogné, B.^{j k} , Dallapiccola, B.^l , Distelmaier, F.^m , Elmslie, F.ⁿ , Faivre, L.^{g o} , Haack, T.B.^h , Harrison, V.^p , Henderson, A.^q , Hunt, D.^p , Isidor, B.^j , Joset, P.^{c d} , Kumada, S.^r , Lachmeijer, A.M.A.^s , Lees, M.^t , Lynch, S.A.^u , Martinez, F.^v , Matsumoto, N.^w , McDougall, C.^x , Mefford, H.C.^y , Miyake, N.^w , Myers, C.T.^y , Moutton, S.^{g o} , Nesbitt, A.^z , Novelli, A.^l , Orellana, C.^v , Rauch, A.^{c d} , Rosello, M.^v , Saida, K.^w , Santani, A.B.^{z aa} , Sarkar, A.^ab , Scheffer, I.E.^ac , Shinawi, M.^ad , Steindl, K.^{c d} , Symonds, J.D.^ae , Zackai, E.H.^x , Reis, A.^a , Sticht, H.^af , Zweier, C.^a , University of Washington Center for Mendelian Genomics^ah , DDD Study^ag  

^a Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany
^b Department of Paediatrics and Child Health, University of Otago, Wellington, 6242, New Zealand
^c Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, 8952, Switzerland
^d radiz – “Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich,”, Zurich, 8032, Switzerland
^e Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, Calambrone, Pisa 56128, Italy
^f Department of Clinical Genetics, Odense University Hospital, Odense, 5000, Denmark
^g INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon, 21079, France
^h Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, 72076, Germany
ⁱ Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom
^j Department of Medical Genetics, CHU Nantes, Nantes, 44093, France
^k l’Institut du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, 44007, France
^l Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, 00146, Italy
^m Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital Düsseldorf, Medical Faculty, Heinrich Heine University, Düsseldorf, 40225, Germany
ⁿ South West Thames Regional Genetics Service, St. George’s, University of London, London, SW17 0RE, United Kingdom
^o Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, Dijon, 21000, France
^p Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, SO16 5YA, United Kingdom
^q Northern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle upon Tyne, NE1 3BZ, United Kingdom
^r Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, 183-0042, Japan
^s Department of Genetics, University Medical Center Utrecht, PO Box 85090, Utrecht, AB 3508, Netherlands
^t North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London, WC1N 3JH, United Kingdom
^u Dept of Clinical Genetics, Temple Street Children’s Hospital Dublin 1, Dublin, D12 V004, Ireland
^v Unidad de Genética, Hospital Universitario y Politécnico La Fe, Avda Fernando Abril Martorell 106, Valencia, 46026, Spain
^w Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
^x Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
^y Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, United States
^z Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
^aa Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
^ab Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham, NG5 1PB, United Kingdom
^ac Departments of Medicine and Paediatrics, Austin Health and Royal Children’s Hospital, The University of Melbourne, Parkville, VIC 3050, Australia
^ad Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
^ae Paediatric Neurosciences Research Group, Fraser of Allander Neurosciences Unit, Royal Hospital for Children, Glasgow, G51 4TF, United Kingdom
^af Institute of Biochemistry, Emil-Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany
^ag Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom

Abstract
Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features. © 2018 American Society of Human Genetics

Author Keywords
FBXO11;  intellectual disability;  neurodevelopmental disorder

Document Type: Article
Source: Scopus

Antidepressive and anxiolytic effects of ostruthin, a TREK-1 channel activator
(2018) PLoS ONE, 13 (8), art. no. e0201092, . 

Joseph, A.^{a d} , Thuy, T.T.T.^b , Thanh, L.T.^b , Okada, M.^{a c}

^a Department of Physiology, Kansai Medical University, Osaka, Japan
^b Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology, Hanoi, Viet Nam
^c Department of Medical Life Science, College of Life Science, Kurashiki University of Science and the Arts, Kurashiki, Okayama, Japan
^d Division of Molecular Oncology, School of Medicine, Washington University, St Louis, MO, United States

Abstract
We screened a library of botanical compounds purified from plants of Vietnam for modulators of the activity of a two-pore domain K+ channel, TREK-1, and we identified a hydroxycoumarin- related compound, ostruthin, as an activator of this channel. Ostruthin increased whole-cell TREK-1 channel currents in 293T cells at a low concentration (EC50 = 5.3 μM), and also activity of the TREK-2 channel (EC50 = 3.7 mM). In contrast, ostruthin inhibited other K+ channels, e.g. human ether-à-go-go-related gene (HERG1), inward-rectifier (Kir2.1), voltage-gated (Kv1.4), and two-pore domain (TASK-1) at higher concentrations, without affecting voltage-gated potassium channel (KCNQ1 and 3). We tested the effect of this compound on mouse anxiety- and depression-like behaviors and found anxiolytic activity in the open-field, elevated plus maze, and light/dark box tests. Of note, ostruthin also showed antidepressive effects in the forced swim and tail suspension tests, although previous studies reported that inhibition of TREK-1 channels resulted in an antidepressive effect. The anxiolytic and antidepressive effect was diminished by co-administration of a TREK-1 blocker, amlodipine, indicating the involvement of TREK-1 channels. Administration of ostruthin suppressed the stress-induced increase in anti-c-Fos immunoreactivity in the lateral septum, without affecting immunoreactivity in other mood disorder-related nuclei, e.g. the amygdala, paraventricular nuclei, and dorsal raphe nucleus. Ostruthin may exert its anxiolytic and antidepressive effects through a different mechanism from current drugs. Copyright © 2018 Joseph et al.

Document Type: Article
Source: Scopus
Access Type: Open Access

Use of medical care biases associations between Parkinson disease and other medical conditions
(2018) Neurology, 90 (24), pp. e2146-e2154. Cited 1 time.

Gross, A.^a , Racette, B.A.^{a b} , Camacho-Soto, A.^a , Dube, U.^a , Nielsen, S.S.^a

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa

Abstract
Objective To examine how use of medical care biases the well-established associations between Parkinson disease (PD) and smoking, smoking-related cancers, and selected positively associated comorbidities. Methods We conducted a population-based, case-control study of 89,790 incident PD cases and 118,095 randomly selected controls, all Medicare beneficiaries aged 66 to 90 years. We ascertained PD and other medical conditions using ICD-9-CM codes from comprehensive claims data for the 5 years before PD diagnosis/reference. We used logistic regression to estimate age-, sex-, and race-adjusted odds ratios (ORs) between PD and each other medical condition of interest. We then examined the effect of also adjusting for selected geographic-or individual-level indicators of use of care. Results Models without adjustment for use of care and those that adjusted for geographic-level indicators produced similar ORs. However, adjustment for individual-level indicators consistently decreased ORs: Relative to ORs without adjustment for use of care, all ORs were between 8% and 58% lower, depending on the medical condition and the individual-level indicator of use of care added to the model. ORs decreased regardless of whether the established association is known to be positive or inverse. Most notably, smoking and smoking-related cancers were positively associated with PD without adjustment for use of care, but appropriately became inversely associated with PD with adjustment for use of care. Conclusion Use of care should be considered when evaluating associations between PD and other medical conditions to ensure that positive associations are not attributable to bias and that inverse associations are not masked. © 2018 American Academy of Neurology.

Document Type: Article
Source: Scopus