title: Hidden Genetic Variation in LCA9-Associated Congenital Blindness Explained by 5'UTR Mutations and Copy-Number Variations of NMNAT1.
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 emphasized a shift from coding to noncoding regulatory mutations and repeat-mediated SVs in the molecular pathogenesis of heterogeneous recessive disorders such as hereditary blindness.
authors: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors: Frauke
authors: F
authors: Coppieters
authors: Institut Jacques Monod, UMR 7592 CNRS-Université Paris Diderot, Paris, France.
authors: Anne Laure
authors: AL
authors: Todeschini
authors: Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors: Takuro
authors: T
authors: Fujimaki
authors: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors: Annelot
authors: A
authors: Baert
authors: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors: Marieke
authors: M
authors: De Bruyne
authors: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors: Caroline
authors: C
authors: Van Cauwenbergh
authors: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors: Hannah
authors: H
authors: Verdin
authors: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors: Miriam
authors: M
authors: Bauwens
authors: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors: Maté
authors: M
authors: Ongenaert
authors: Department of Ophthalmology, Mie University Graduate School of Medicine, Mie, Japan.
authors: Mineo
authors: M
authors: Kondo
authors: Department of Ophthalmology, Queen Fabiola Children's University Hospital, Brussels, Belgium.
authors: Françoise
authors: F
authors: Meire
authors: Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors: Akira
authors: A
authors: Murakami
authors: Institut Jacques Monod, UMR 7592 CNRS-Université Paris Diderot, Paris, France.
authors: Reiner A
authors: RA
authors: Veitia
authors: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.|Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.|Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors: Bart P
authors: BP
authors: Leroy
authors: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors: Elfride
authors: E
authors: De Baere
mesh_terms: D020121:5' Untranslated Regions; D000483:Alleles; D020087:Alu Elements; D002648:Child; D056905:Chromosome Breakpoints; D002874:Chromosome Mapping; D019295:Computational Biology / Q000379:methods; D003241:Consanguinity; D056915:DNA Copy Number Variations; D005091:Exons; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D057130:Leber Congenital Amaurosis / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D020121:5' Untranslated Regions; D047908:Intracellular Signaling Peptides and Proteins; C447999:LZIC protein, human; D012333:RNA, Messenger; C484007:NMNAT1 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase
keywords: 5′UTR variants; Alu-mediated deletions; LCA9; Leber congenital amaurosis; NMNAT1