Advanced search
1 file | 859.34 KB

Hidden genetic variation in LCA9-associated congenital blindness explained by 5′UTR mutations and copy-number variations of NMNAT1

(2015) HUMAN MUTATION. 36(12). p.1188-1196
Author
Organization
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.
Keywords
LCA9, Leber congenital amaurosis, NMNAT1, 5 ' UTR variants, Alu-mediated deletions, IMPERFECTA TYPE-V, RETINITIS-PIGMENTOSA, AMAUROSIS, DISEASE, DEGENERATION, MECHANISMS, EXPRESSION, 5'-UTR, TOOL, PCR

Downloads

  • humu22899.pdf
    • full text
    • |
    • open access
    • |
    • PDF
    • |
    • 859.34 KB

Citation

Please use this url to cite or link to this publication:

Chicago
Coppieters, Frauke, Anne Laure Todeschini, Takuro Fujimaki, Annelot Baert, Marieke De Bruyne, Caroline Van Cauwenbergh, Hannah Verdin, et al. 2015. “Hidden Genetic Variation in LCA9-associated Congenital Blindness Explained by 5′UTR Mutations and Copy-number Variations of NMNAT1.” Human Mutation 36 (12): 1188–1196.
APA
Coppieters, F., Todeschini, A. L., Fujimaki, T., Baert, A., De Bruyne, M., Van Cauwenbergh, C., Verdin, H., et al. (2015). Hidden genetic variation in LCA9-associated congenital blindness explained by 5′UTR mutations and copy-number variations of NMNAT1. HUMAN MUTATION, 36(12), 1188–1196.
Vancouver
1.
Coppieters F, Todeschini AL, Fujimaki T, Baert A, De Bruyne M, Van Cauwenbergh C, et al. Hidden genetic variation in LCA9-associated congenital blindness explained by 5′UTR mutations and copy-number variations of NMNAT1. HUMAN MUTATION. 2015;36(12):1188–96.
MLA
Coppieters, Frauke et al. “Hidden Genetic Variation in LCA9-associated Congenital Blindness Explained by 5′UTR Mutations and Copy-number Variations of NMNAT1.” HUMAN MUTATION 36.12 (2015): 1188–1196. Print.
@article{7083235,
  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{\textrangle}T. Moreover, an adjacent 5'UTR variant, c.-69C{\textrangle}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.},
  author       = {Coppieters, Frauke and Todeschini, Anne Laure and Fujimaki, Takuro and Baert, Annelot and De Bruyne, Marieke and Van Cauwenbergh, Caroline and Verdin, Hannah and Bauwens, Miriam and Ongenaert, Mat{\'e} and Kondo, Mineo and Meire, Fran\c{c}oise and Murakami, Akira and Veitia, Reiner A and Leroy, Bart and De Baere, Elfride},
  issn         = {1059-7794},
  journal      = {HUMAN MUTATION},
  language     = {eng},
  number       = {12},
  pages        = {1188--1196},
  title        = {Hidden genetic variation in LCA9-associated congenital blindness explained by 5{\textquotesingle}UTR mutations and copy-number variations of NMNAT1},
  url          = {http://dx.doi.org/10.1002/humu.22899},
  volume       = {36},
  year         = {2015},
}

Altmetric
View in Altmetric
Web of Science
Times cited: