Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice.
Adult
Animals
Child
Child, Preschool
Exons
Family
Female
Frameshift Mutation
/ genetics
Genetic Variation
/ genetics
Glaucoma, Angle-Closure
/ genetics
Humans
Hyperopia
/ genetics
Male
Membrane Proteins
/ genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Microphthalmos
/ genetics
Middle Aged
Pedigree
RNA Splice Sites
/ genetics
Refractive Errors
/ genetics
Retinal Degeneration
/ genetics
Transcription Factors
/ genetics
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
11
12
2018
accepted:
09
04
2019
revised:
20
05
2019
pubmed:
3
5
2019
medline:
27
11
2019
entrez:
4
5
2019
Statut:
epublish
Résumé
Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development.
Identifiants
pubmed: 31048900
doi: 10.1371/journal.pgen.1008130
pii: PGENETICS-D-18-02347
pmc: PMC6527243
doi:
Substances chimiques
Membrane Proteins
0
Myrf protein, human
0
RNA Splice Sites
0
TMEM98 protein, human
0
Transcription Factors
0
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
e1008130Subventions
Organisme : NEI NIH HHS
ID : R01 EY011671
Pays : United States
Organisme : NCATS NIH HHS
ID : KL2 TR001879
Pays : United States
Organisme : Department of Health
Pays : United Kingdom
Organisme : NEI NIH HHS
ID : R56 EY011671
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY009580
Pays : United States
Organisme : NEI NIH HHS
ID : P30 EY007003
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Prog Retin Eye Res. 2009 May;28(3):206-26
pubmed: 19398034
Eye (Lond). 2016 Jan;30(1):120-6
pubmed: 26493039
PLoS Biol. 2013;11(8):e1001624
pubmed: 23966832
Ophthalmology. 2011 Aug;118(8):1653-60
pubmed: 21529956
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Acta Neuropathol. 2017 Sep;134(3):403-422
pubmed: 28631093
Genes Cells. 2005 Jul;10(7):743-52
pubmed: 15966904
Am J Med Genet A. 2018 Apr;176(4):969-972
pubmed: 29446546
Am J Med Genet A. 2011 May;155A(5):1001-6
pubmed: 21484995
Hum Mol Genet. 2002 Aug 1;11(16):1879-86
pubmed: 12140190
Bioinformatics. 2012 Jun 15;28(12):i197-206
pubmed: 22689761
Nucleic Acids Res. 2017 May 19;45(9):5112-5125
pubmed: 28160598
Cold Spring Harb Protoc. 2014 Jun 02;2014(6):655-8
pubmed: 24890205
Nature. 2009 Sep 10;461(7261):272-6
pubmed: 19684571
Am J Ophthalmol. 2008 Aug;146(2):323-328
pubmed: 18554571
PLoS Biol. 2013;11(8):e1001625
pubmed: 23966833
PLoS Genet. 2013 Oct;9(10):e1003907
pubmed: 24204311
Nat Neurosci. 2016 Sep;19(9):1210-1217
pubmed: 27455109
JAMA Ophthalmol. 2014 Aug;132(8):970-7
pubmed: 24852644
Nucleic Acids Res. 2001 Jan 1;29(1):308-11
pubmed: 11125122
Curr Opin Ophthalmol. 2014 Mar;25(2):89-92
pubmed: 24463418
Mol Reprod Dev. 2015 Jul-Aug;82(7-8):518-29
pubmed: 26153368
Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12758-63
pubmed: 11050159
Sci Rep. 2017 Nov 23;7(1):16151
pubmed: 29170418
Genome Res. 2010 Sep;20(9):1297-303
pubmed: 20644199
Mol Vis. 2015 Sep 01;21:1017-23
pubmed: 26392740
Genes Dev. 1994 Jun 15;8(12):1434-47
pubmed: 7926743
Invest Ophthalmol Vis Sci. 2001 May;42(6):1232-6
pubmed: 11328732
Pan Afr Med J. 2009 Dec 17;3:20
pubmed: 21532729
Hum Mol Genet. 1998 Sep;7(9):1517-25
pubmed: 9700209
Invest Ophthalmol Vis Sci. 2007 May;48(5):1959-67
pubmed: 17460247
Ophthalmology. 2010 Mar;117(3):417-23
pubmed: 20031227
Hum Mol Genet. 2018 Oct 1;27(19):3325-3339
pubmed: 30239781
J Cell Sci. 2013 Nov 15;126(Pt 22):5247-58
pubmed: 24046445
Nat Rev Genet. 2011 Sep 27;12(11):745-55
pubmed: 21946919
Ann Neurol. 2018 Jan;83(1):98-106
pubmed: 29265453
Am J Hum Genet. 2008 Jan;82(1):19-31
pubmed: 18179881
J Med Genet. 2009 Sep;46(9):620-5
pubmed: 18611979
Br J Ophthalmol. 2008 Nov;92(11):1467-70
pubmed: 18703557
Glia. 2016 Dec;64(12):2120-2132
pubmed: 27532821
Genesis. 2006 Aug;44(8):361-3
pubmed: 16850473
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
Ophthalmic Genet. 2008 Mar;29(1):1-9
pubmed: 18363166
Hum Mol Genet. 2003 Sep 1;12(17):2179-89
pubmed: 12915475
BMJ Open. 2013 Jul 24;3(7):
pubmed: 23883889
Hum Mutat. 2014 Feb;35(2):151-64
pubmed: 24323938
J Neurosci. 2018 Nov 14;38(46):9829-9839
pubmed: 30249802
Pediatr Cardiol. 2010 Jan;31(1):1-6
pubmed: 19727926
J Cataract Refract Surg. 2004 Mar;30(3):584-90
pubmed: 15050253
Am J Epidemiol. 2014 Sep 15;180(6):562-4
pubmed: 25150271
Invest Ophthalmol Vis Sci. 2018 Jul 2;59(8):3209-3219
pubmed: 29971438
Genome Res. 2009 Sep;19(9):1665-74
pubmed: 19602640
Sci Rep. 2018 Aug 30;8(1):13075
pubmed: 30166609
J Cataract Refract Surg. 2015 Nov;41(11):2565-75
pubmed: 26703508
Am J Ophthalmol. 2017 Oct;182:81-89
pubmed: 28751151
Optom Vis Sci. 2017 Mar;94(3):387-394
pubmed: 28005683
Invest Ophthalmol Vis Sci. 2019 Jul 1;60(8):2875-2887
pubmed: 31266059
Ann Transl Med. 2016 May;4(10):198
pubmed: 27294094
J Neurosci. 2012 Sep 5;32(36):12528-42
pubmed: 22956843
Mol Vis. 2006 Dec 04;12:1483-9
pubmed: 17167404
Eur J Hum Genet. 2000 Apr;8(4):286-92
pubmed: 10854112
Optom Vis Sci. 2012 Mar;89(3):296-303
pubmed: 22246334
Bioinformatics. 2011 Aug 1;27(15):2156-8
pubmed: 21653522
J Gen Physiol. 2006 May;127(5):577-89
pubmed: 16636205
Hum Mol Genet. 2011 Apr 1;20(7):1411-23
pubmed: 21245082
Nucleic Acids Res. 2014 Jan;42(Database issue):D802-9
pubmed: 24194600
Arch Ophthalmol. 2009 May;127(5):649-55
pubmed: 19433716
Am J Hum Genet. 2011 Mar 11;88(3):382-90
pubmed: 21397065
Gene. 2006 Feb 1;366(2):219-27
pubmed: 16226402
Invest Ophthalmol Vis Sci. 2011 Aug 29;52(9):6898-910
pubmed: 21757580
Am J Ophthalmol. 2007 Oct;144(4):487-96
pubmed: 17707330
Nat Genet. 2014 Mar;46(3):310-5
pubmed: 24487276
Mol Vis. 2013 Nov 07;19:2217-26
pubmed: 24227917
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
Cochrane Database Syst Rev. 2014 Aug 18;(8):CD007738
pubmed: 25133974
BMC Dev Biol. 2001;1:4
pubmed: 11299042
PLoS Genet. 2018 Dec 10;14(12):e1007822
pubmed: 30532227
Vision Res. 2004;44(16):1857-67
pubmed: 15145680
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
Prog Retin Eye Res. 2009 May;28(3):187-205
pubmed: 19375515
Hum Gene Ther. 2012 Apr;23(4):367-76
pubmed: 22142163
Ophthalmic Genet. 2005 Dec;26(4):153-5
pubmed: 16352474
Ophthalmology. 2003 Oct;110(10):1880-9
pubmed: 14522758
Am J Hum Genet. 1998 Nov;63(5):1411-8
pubmed: 9792868
J Neurosci. 1998 Nov 1;18(21):8936-46
pubmed: 9786999
Methods Mol Biol. 2019;1834:45-58
pubmed: 30324435
BMC Ophthalmol. 2016 May 01;16(1):47
pubmed: 27138378
Am J Med Genet A. 2018 Sep;176(9):2041-2043
pubmed: 30070761
Retina. 2016 Aug;36(8):1586-95
pubmed: 26716959
Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9553-8
pubmed: 15976030
J Ophthalmol. 2018 May 9;2018:2735465
pubmed: 29862063
Brief Funct Genomics. 2014 Sep;13(5):378-83
pubmed: 25024279
Pediatr Clin North Am. 1987 Dec;34(6):1425-37
pubmed: 3317238
Cell. 2009 Jul 10;138(1):172-85
pubmed: 19596243
Exp Eye Res. 2011 Oct;93(4):482-90
pubmed: 21726551
Optom Vis Sci. 2016 Jan;93(1):19-26
pubmed: 26583794
Ophthalmology. 1998 Jul;105(7):1274-80
pubmed: 9663233
Nat Genet. 2011 Jun;43(6):579-84
pubmed: 21532570
Lancet Glob Health. 2017 Dec;5(12):e1221-e1234
pubmed: 29032195
Invest Ophthalmol Vis Sci. 2018 Oct 1;59(12):5225-5236
pubmed: 30372751
PLoS Genet. 2018 Mar 12;14(3):e1007244
pubmed: 29529029
Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3683-9
pubmed: 15452077
Genet Med. 2017 Feb;19(2):249-255
pubmed: 27854360