TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila.
Alleles
Amino Acid Sequence
Animals
Developmental Disabilities
/ genetics
Drosophila Proteins
/ antagonists & inhibitors
Drosophila melanogaster
/ genetics
Eye Diseases, Hereditary
/ genetics
Female
Gene Dosage
Gene Expression Regulation, Developmental
Genome, Human
Humans
Infant
Infant, Newborn
Intellectual Disability
/ genetics
Karyopherins
/ antagonists & inhibitors
Male
Musculoskeletal Abnormalities
/ genetics
Mutation
Neurons
/ metabolism
RNA, Small Interfering
/ genetics
Sequence Alignment
Sequence Homology, Amino Acid
Whole Genome Sequencing
beta Karyopherins
/ genetics
ran GTP-Binding Protein
/ genetics
Drosophila
Importin-3
Karyopherin-β2b
TNPO1
TNPO2
Transportin
global developmental delays
intellectual disability
nucleocytoplasmic shuttling
rare disease
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
02 09 2021
02 09 2021
Historique:
received:
28
01
2021
accepted:
27
06
2021
pubmed:
28
7
2021
medline:
16
9
2021
entrez:
27
7
2021
Statut:
ppublish
Résumé
Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.
Identifiants
pubmed: 34314705
pii: S0002-9297(21)00267-6
doi: 10.1016/j.ajhg.2021.06.019
pmc: PMC8456166
pii:
doi:
Substances chimiques
Drosophila Proteins
0
Karyopherins
0
RNA, Small Interfering
0
TNPO2 protein, human
0
Tnpo protein, Drosophila
0
beta Karyopherins
0
ran GTP-Binding Protein
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1669-1691Subventions
Organisme : NHGRI NIH HHS
ID : U01 HG007672
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS043124
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM067858
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD103555
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : Department of Health
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : U54 NS093793
Pays : United States
Organisme : NIH HHS
ID : R24 OD022005
Pays : United States
Informations de copyright
Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. Y.S. and A.B. are employees of GeneDx, Inc.
Références
Mech Ageing Dev. 2009 Aug;130(8):547-52
pubmed: 19486910
Mol Biol Cell. 2007 Jul;18(7):2619-29
pubmed: 17475777
J Biol Chem. 2011 Jul 22;286(29):25983-91
pubmed: 21646354
Cell. 2018 Apr 19;173(3):677-692.e20
pubmed: 29677512
Nat Struct Mol Biol. 2007 May;14(5):452-4
pubmed: 17435768
Science. 2006 Dec 15;314(5806):1747-51
pubmed: 17138868
J Cell Sci. 2016 Oct 15;129(20):3922-3934
pubmed: 27633000
J Neurobiol. 1991 Jul;22(5):443-61
pubmed: 1716300
FEBS Lett. 2014 May 21;588(10):1857-68
pubmed: 24780099
Hum Mol Genet. 2019 Nov 15;28(22):3777-3791
pubmed: 31509188
Eur J Hum Genet. 2018 Sep;26(9):1388-1391
pubmed: 29795476
Mol Syst Biol. 2017 Dec 18;13(12):962
pubmed: 29254951
Mol Genet Genomic Med. 2016 Apr 03;4(4):465-74
pubmed: 27441201
J Biol Chem. 2015 Jul 17;290(29):17967-17984
pubmed: 26060253
Nat Cell Biol. 2010 Jul;12(7):703-10
pubmed: 20526328
Genetics. 2017 Sep;207(1):9-27
pubmed: 28874452
Nat Genet. 2014 Sep;46(9):944-50
pubmed: 25086666
Nat Commun. 2015 Aug 11;6:7924
pubmed: 26263051
Dev Biol. 2001 Oct 1;238(1):47-63
pubmed: 11783993
Nat Genet. 2019 May;51(5):772-776
pubmed: 30962618
J Cell Sci. 2020 Feb 12;133(3):
pubmed: 31932502
Nature. 2007 Jul 12;448(7150):151-6
pubmed: 17625558
Mol Cell Biol. 1998 Jul;18(7):4141-8
pubmed: 9632798
Am J Hum Genet. 2017 Jul 6;101(1):23-36
pubmed: 28625504
Nature. 2003 Aug 7;424(6949):689-94
pubmed: 12894213
Nature. 2007 Mar 29;446(7135):557-61
pubmed: 17361131
Am J Hum Genet. 2020 Aug 6;107(2):352-363
pubmed: 32693025
J Biol Chem. 2010 Oct 1;285(40):30548-57
pubmed: 20663864
Mol Cell. 2013 Feb 21;49(4):730-42
pubmed: 23333309
Acta Neuropathol Commun. 2019 Apr 25;7(1):62
pubmed: 31023341
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Semin Pediatr Neurol. 2015 Jun;22(2):113-25
pubmed: 26072341
Am J Hum Genet. 2017 Jun 1;100(6):843-853
pubmed: 28502612
Annu Rev Neurosci. 2020 Jul 8;43:465-484
pubmed: 32283995
EMBO J. 2012 Nov 14;31(22):4258-75
pubmed: 22968170
J Neurosci. 2020 Oct 14;40(42):7999-8024
pubmed: 32928889
Mech Dev. 2017 Apr;144(Pt A):23-32
pubmed: 27784612
Cytoskeleton (Hoboken). 2020 Mar;77(3-4):110-128
pubmed: 31970897
Am J Hum Genet. 2010 May 14;86(5):749-64
pubmed: 20466091
Am J Hum Genet. 2020 Apr 2;106(4):570-583
pubmed: 32197074
Mol Cell Proteomics. 2008 Jul;7(7):1254-69
pubmed: 18353765
Sci Rep. 2016 Jul 07;6:28998
pubmed: 27383233
Genesis. 2002 Sep-Oct;34(1-2):58-61
pubmed: 12324948
Brain. 2017 Jan;140(1):13-26
pubmed: 27497493
J Biol Chem. 2007 Oct 19;282(42):31046-59
pubmed: 17681951
Neuron. 2010 May 27;66(4):523-35
pubmed: 20510857
BMC Bioinformatics. 2011 Aug 31;12:357
pubmed: 21880147
Gene. 2000 Aug 8;253(2):151-60
pubmed: 10940552
J Undergrad Neurosci Educ. 2012 Fall;11(1):A149-57
pubmed: 23494679
BMC Genet. 2014 Apr 16;15:46
pubmed: 24739137
J Med Genet. 2014 Jan;51(1):45-54
pubmed: 24203977
Oncogene. 2008 Oct 16;27(47):6102-9
pubmed: 18679426
Nucleic Acids Res. 1997 Sep 15;25(18):3665-71
pubmed: 9278488
Nature. 2017 Feb 23;542(7642):433-438
pubmed: 28135719
Dev Growth Differ. 2007 Apr;49(3):215-27
pubmed: 17394600
J Genet. 2015 Sep;94(3):407-16
pubmed: 26440079
J Cell Sci. 2014 Mar 1;127(Pt 5):1092-103
pubmed: 24413177
Nat Neurosci. 2019 Jun;22(6):863-874
pubmed: 31110321
Adv Clin Exp Med. 2015 May-Jun;24(3):525-30
pubmed: 26467144
Front Cell Dev Biol. 2016 Jan 11;3:82
pubmed: 26793706
Am J Hum Genet. 2020 Dec 3;107(6):1096-1112
pubmed: 33232675
Am J Hum Genet. 2019 Aug 1;105(2):413-424
pubmed: 31327508
Cell Rep. 2018 Jul 24;24(4):987-1000.e7
pubmed: 30044993
Elife. 2018 Mar 22;7:
pubmed: 29565247
Mol Biol Cell. 2014 Apr;25(7):992-1009
pubmed: 24478460
N Engl J Med. 2018 Nov 29;379(22):2131-2139
pubmed: 30304647
Nat Cell Biol. 2009 Jul;11(7):815-24
pubmed: 19543274
Acta Neuropathol Commun. 2015 Apr 25;3:24
pubmed: 25907258
Nucleic Acids Res. 2014 Jan;42(Database issue):D802-9
pubmed: 24194600
J Comp Neurol. 2011 Jun 15;519(9):1770-80
pubmed: 21452213
Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894
pubmed: 30371827
Hum Mutat. 2017 Mar;38(3):289-296
pubmed: 27957775
EMBO J. 2010 Aug 18;29(16):2841-57
pubmed: 20606625
Am J Med Genet A. 2008 May 15;146A(10):1299-306
pubmed: 18398855
Genet Mol Res. 2012 Aug 06;11(3):1997-2002
pubmed: 22911584
Science. 2006 Apr 21;312(5772):440-3
pubmed: 16627745
J Comp Neurol. 2009 Nov 1;517(1):15-36
pubmed: 19711379
Mol Cell Proteomics. 2013 Jan;12(1):145-57
pubmed: 23087160
Neurobiol Dis. 2015 Feb;74:76-88
pubmed: 25447237
N Engl J Med. 2012 Nov 15;367(20):1921-9
pubmed: 23033978
J Biol Chem. 2007 Sep 21;282(38):27685-92
pubmed: 17652081
J Biol Chem. 2006 Mar 3;281(9):5492-9
pubmed: 16407315
J Vis Exp. 2019 Aug 20;(150):
pubmed: 31498321
Mamm Genome. 2019 Aug;30(7-8):212-216
pubmed: 31444567
J Biol Chem. 2012 Nov 16;287(47):39626-33
pubmed: 23012356
Dev Cell. 2019 Dec 16;51(6):713-729.e6
pubmed: 31735666
Genet Med. 2011 Sep;13(9):777-84
pubmed: 21844811
Cell. 2006 Aug 11;126(3):543-58
pubmed: 16901787
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2918-23
pubmed: 14981248
Chromosoma. 2016 Sep;125(4):573-92
pubmed: 27153833
Hum Mutat. 2015 Oct;36(10):928-30
pubmed: 26220891
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3312-7
pubmed: 17360644
Sci Signal. 2018 Jul 03;11(537):
pubmed: 29970603
Genetics. 2015 Nov;201(3):843-52
pubmed: 26320097
Genetics. 2008 Jan;178(1):215-34
pubmed: 18202369
Elife. 2017 Jan 24;6:
pubmed: 28117667
Sarcoma. 2011;2011:218483
pubmed: 21647358
Pflugers Arch. 2007 Aug;454(5):821-47
pubmed: 17487503
J Cell Sci. 2011 Mar 1;124(Pt 5):718-26
pubmed: 21285245
Neuron. 2017 Jan 4;93(1):115-131
pubmed: 28017472
Nat Neurosci. 2016 Sep;19(9):1194-6
pubmed: 27479843
Nat Genet. 2014 Oct;46(10):1063-71
pubmed: 25217958
Hum Mol Genet. 2019 Nov 21;28(R2):R207-R214
pubmed: 31227826
Front Mol Neurosci. 2017 May 01;10:121
pubmed: 28588446
Mol Biol Cell. 2002 Jul;13(7):2436-47
pubmed: 12134081
Mol Cell Biol. 2009 Mar;29(6):1487-97
pubmed: 19124606
J Cell Sci. 2008 May 15;121(Pt 10):1577-86
pubmed: 18469014
Hum Mutat. 2015 Dec;36(12):1197-204
pubmed: 26350204
RNA. 2004 Apr;10(4):590-9
pubmed: 15037768
Genesis. 2002 Sep-Oct;34(1-2):1-15
pubmed: 12324939
Cell. 2015 Jan 15;160(1-2):177-90
pubmed: 25594180
Nucleic Acids Res. 2018 Jan 4;46(D1):D1062-D1067
pubmed: 29165669
Free Radic Biol Med. 2020 Aug 20;156:45-56
pubmed: 32553752
Cell Death Dis. 2013 Apr 18;4:e599
pubmed: 23598411
PLoS Genet. 2018 Jan 29;14(1):e1007189
pubmed: 29377895