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Autosomal recessive retinitis pigmentosa with homozygous rhodopsin mutation E150K and non-coding cis-regulatory variants in CRX-binding regions of SAMD7

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Abstract
The aim of this study was to unravel the molecular pathogenesis of an unusual retinitis pigmentosa (RP) phenotype observed in a Turkish consanguineous family. Homozygosity mapping revealed two candidate genes, SAMD7 and RHO. A homozygous RHO mutation c.448G > A, p.E150K was found in two affected siblings, while no coding SAMD7 mutations were identified. Interestingly, four non-coding homozygous variants were found in two SAMD7 genomic regions relevant for binding of the retinal transcription factor CRX (CRX-bound regions, CBRs) in these affected siblings. Three variants are located in a promoter CBR termed CBR1, while the fourth is located more downstream in CBR2. Transcriptional activity of these variants was assessed by luciferase assays and electroporation of mouse retinal explants with reporter constructs of wild-type and variant SAMD7 CBRs. The combined CBR2/CBR1 variant construct showed significantly decreased SAMD7 reporter activity compared to the wild-type sequence, suggesting a cis-regulatory effect on SAMD7 expression. As Samd7 is a recently identified Crx-regulated transcriptional repressor in retina, we hypothesize that these SAMD7 variants might contribute to the retinal phenotype observed here, characterized by unusual, recognizable pigment deposits, differing from the classic spicular intraretinal pigmentation observed in other individuals homozygous for p. E150K, and typically associated with RP in general.
Keywords
RETINAL DEGENERATION, LEBER CONGENITAL AMAUROSIS, PAKISTANI FAMILIES, GENE, REVEALS, MODIFIER, GENOME, DYSTROPHIES, EXPRESSION, PRPF31

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Chicago
Van Schil, Kristof, Marcus Karlstetter, Alexander Aslanidis, Katharina Dannhausen, Maleeha Azam, Raheel Qamar, Bart Leroy, Fanny Depasse, Thomas Langmann, and Elfride De Baere. 2016. “Autosomal Recessive Retinitis Pigmentosa with Homozygous Rhodopsin Mutation E150K and Non-coding Cis-regulatory Variants in CRX-binding Regions of SAMD7.” Scientific Reports 18.
APA
Van Schil, K., Karlstetter, M., Aslanidis, A., Dannhausen, K., Azam, M., Qamar, R., Leroy, B., et al. (2016). Autosomal recessive retinitis pigmentosa with homozygous rhodopsin mutation E150K and non-coding cis-regulatory variants in CRX-binding regions of SAMD7. SCIENTIFIC REPORTS, 18.
Vancouver
1.
Van Schil K, Karlstetter M, Aslanidis A, Dannhausen K, Azam M, Qamar R, et al. Autosomal recessive retinitis pigmentosa with homozygous rhodopsin mutation E150K and non-coding cis-regulatory variants in CRX-binding regions of SAMD7. SCIENTIFIC REPORTS. 2016;18.
MLA
Van Schil, Kristof, Marcus Karlstetter, Alexander Aslanidis, et al. “Autosomal Recessive Retinitis Pigmentosa with Homozygous Rhodopsin Mutation E150K and Non-coding Cis-regulatory Variants in CRX-binding Regions of SAMD7.” SCIENTIFIC REPORTS 18 (2016): n. pag. Print.
@article{7178444,
  abstract     = {The aim of this study was to unravel the molecular pathogenesis of an unusual retinitis pigmentosa (RP) phenotype observed in a Turkish consanguineous family. Homozygosity mapping revealed two candidate genes, SAMD7 and RHO. A homozygous RHO mutation c.448G {\textrangle} A, p.E150K was found in two affected siblings, while no coding SAMD7 mutations were identified. Interestingly, four non-coding homozygous variants were found in two SAMD7 genomic regions relevant for binding of the retinal transcription factor CRX (CRX-bound regions, CBRs) in these affected siblings. Three variants are located in a promoter CBR termed CBR1, while the fourth is located more downstream in CBR2. Transcriptional activity of these variants was assessed by luciferase assays and electroporation of mouse retinal explants with reporter constructs of wild-type and variant SAMD7 CBRs. The combined CBR2/CBR1 variant construct showed significantly decreased SAMD7 reporter activity compared to the wild-type sequence, suggesting a cis-regulatory effect on SAMD7 expression. As Samd7 is a recently identified Crx-regulated transcriptional repressor in retina, we hypothesize that these SAMD7 variants might contribute to the retinal phenotype observed here, characterized by unusual, recognizable pigment deposits, differing from the classic spicular intraretinal pigmentation observed in other individuals homozygous for p. E150K, and typically associated with RP in general.},
  articleno    = {21307},
  author       = {Van Schil, Kristof and Karlstetter, Marcus and Aslanidis, Alexander and Dannhausen, Katharina and Azam, Maleeha and Qamar, Raheel and Leroy, Bart and Depasse, Fanny and Langmann, Thomas and De Baere, Elfride},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  language     = {eng},
  pages        = {10},
  title        = {Autosomal recessive retinitis pigmentosa with homozygous rhodopsin mutation E150K and non-coding cis-regulatory variants in CRX-binding regions of SAMD7},
  url          = {http://dx.doi.org/10.1038/srep21307},
  volume       = {18},
  year         = {2016},
}

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