Hidden Genetic Variation in LCA9-Associated Congenital Blindness Explained by 5'UTR Mutations and Copy-Number Variations of NMNAT1

Human Mutation
Frauke CoppietersElfride De Baere

Abstract

Leber congenital amaurosis (LCA) is a severe autosomal-recessive retinal dystrophy leading to congenital blindness. A recently identified LCA gene is NMNAT1, located in the LCA9 locus. Although most mutations in blindness genes are coding variations, there is accumulating evidence for hidden noncoding defects or structural variations (SVs). The starting point of this study was an LCA9-associated consanguineous family in which no coding mutations were found in the LCA9 region. Exploring the untranslated regions of NMNAT1 revealed a novel homozygous 5'UTR variant, c.-70A>T. Moreover, an adjacent 5'UTR variant, c.-69C>T, was identified in a second consanguineous family displaying a similar phenotype. Both 5'UTR variants resulted in decreased NMNAT1 mRNA abundance in patients' lymphocytes, and caused decreased luciferase activity in human retinal pigment epithelial RPE-1 cells. Second, we unraveled pseudohomozygosity of a coding NMNAT1 mutation in two unrelated LCA patients by the identification of two distinct heterozygous partial NMNAT1 deletions. Molecular characterization of the breakpoint junctions revealed a complex Alu-rich genomic architecture. Our study uncovered hidden genetic variation in NMNAT1-associated LCA and emphas...Continue Reading

References

May 29, 2000·Trends in Genetics : TIG·P RiceA Bleasby
May 8, 2003·European Journal of Human Genetics : EJHG·T Jeffrey KeenChris F Inglehearn
Jun 4, 2005·Developmental Biology·Wilson K Clements, David Kimelman
Jul 18, 2006·Nucleic Acids Research·Oleg KikinParamjeet S Bagga
Feb 9, 2007·Journal of Evaluation in Clinical Practice·Ken R TilashalskiMark S Litaker
May 9, 2007·Nucleic Acids Research·Andreas UntergasserJack A M Leunissen
Jun 5, 2007·Nature Genetics·Anneke I den HollanderRonald Roepman
Jul 18, 2008·Progress in Retinal and Eye Research·Anneke I den HollanderFrans P M Cremers
Jul 15, 2009·Nature Reviews. Genetics·P J HastingsGrzegorz Ira
Dec 9, 2009·Methods : a Companion to Methods in Enzymology·Stefaan DerveauxJan Hellemans
Jan 12, 2010·Methods : a Companion to Methods in Enzymology·Barbara D'haeneJan Hellemans
Mar 30, 2010·Annual Review of Neuroscience·Michael P Coleman, Marc R Freeman
Aug 7, 2010·Human Mutation·Frauke CoppietersElfride De Baere
Apr 27, 2011·Investigative Ophthalmology & Visual Science·Juan I PierasGuillermo Antiñolo
Sep 29, 2011·Nature Biotechnology·Michael J ClarkMichael Snyder
Apr 4, 2012·Current Protocols in Human Genetics·R Z CerR M Stephens
Jun 23, 2012·Human Molecular Genetics·Anna M RoseShomi S Bhattacharya
Jul 31, 2012·Nature Genetics·Marni J FalkEric A Pierce
Aug 7, 2012·American Journal of Human Genetics·Tae-Joon ChoJung-Wook Kim
Nov 15, 2012·Methods in Molecular Biology·Kornelia NevelingRob W J Collin
Jan 15, 2014·Human Molecular Genetics·Xue ChenChen Zhao
Jan 28, 2014·American Journal of Human Genetics·Kathleen A WilliamsonDavid R Fitzpatrick
Mar 15, 2014·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Frauke CoppietersElfride De Baere
May 3, 2014·Neurobiology of Disease·Cheng FangGary Banker
May 17, 2014·JAMA Ophthalmology·Anna M SiemiatkowskaFrans P M Cremers
Aug 7, 2014·Japanese Journal of Ophthalmology·Takahide SuzukiAkira Murakami

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Citations

Mar 9, 2017·Human Mutation·Alina RadziwonIan M MacDonald
May 17, 2017·Human Molecular Genetics·G Jane FarrarPete Humphries
Jan 12, 2020·Pigment Cell & Melanoma Research·Mutsumi SuganumaMasashi Akiyama
Jul 28, 2017·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Kristof Van SchilElfride De Baere
Feb 11, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Erin ZampaglioneKinga M Bujakowska
Aug 11, 2020·Molecular Therapy. Methods & Clinical Development·Scott H GreenwaldEric A Pierce
Jun 3, 2021·International Journal of Molecular Sciences·Adrian DockeryG Jane Farrar

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Methods Mentioned

BETA
chip
genotyping
transfection
Assay
PCR

Software Mentioned

RepeatAround
UCSC genome browser
qbase +
PrimerXL
QGRS Mapper
qbase
Biogazelle
BLAST2
PLINK
SeqScape

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