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Putative digenic in...
Putative digenic inheritance of heterozygous RP1L1 and C2orf71 null mutations in syndromic retinal dystrophy
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- Liu, Yangfan P. (författare)
- Center for Human Disease Modeling, Duke University School of Medicine, Durham NC, USA
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- Bosch, Danielle G. M. (författare)
- Bartiméus, Institute for the Visually Impaired, Zeist, The Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
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- Siemiatkowska, Anna M. (författare)
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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- Dahl Rendtorff, Nanna (författare)
- Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, ICMM, University of Copenhagen, Copenhagen, Denmark; Department of Audiology, Bispebjerg Hospital and Rigshospitalet, Copenhagen, Denmark
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- Boonstra, F. Nienke (författare)
- Bartiméus, Institute for the Visually Impaired, Zeist, The Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
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- Möller, Claes, 1950- (författare)
- Örebro universitet,Institutionen för hälsovetenskaper,Region Örebro län,Audiological Research Centre, Örebro University Hospital, Örebro, Sweden
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- Tranebjaerg, Lisbeth (författare)
- Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine ICMM, University of Copenhagen, Copenhagen, Denmark; Department of Audiology, Bispebjerg Hospital and Rigshospitalet, Copenhagen, Denmark
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- Katsanis, Nicholas (författare)
- Center for Human Disease Modeling, Duke University School of Medicine, Durham NC, USA
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- Cremers, Frans P. M. (författare)
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
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(creator_code:org_t)
- 2016-03-30
- 2017
- Engelska.
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Ingår i: Ophthalmic Genetics. - Philadelphia, USA : Taylor & Francis. - 1381-6810 .- 1744-5094. ; 38:2, s. 127-132
- Relaterad länk:
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https://doi.org/10.3...
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https://www.tandfonl...
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https://urn.kb.se/re...
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https://doi.org/10.3...
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Abstract
Ämnesord
Stäng
- Background: Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration and can occur in non-syndromic and syndromic forms. Syndromic RP is accompanied by other symptoms such as intellectual disability, hearing loss, or congenital abnormalities. Both forms are known to exhibit complex genetic interactions that can modulate the penetrance and expressivity of the phenotype.Materials and methods: In an individual with atypical RP, hearing loss, ataxia and cerebellar atrophy, whole exome sequencing was performed. The candidate pathogenic variants were tested by developing an in vivo zebrafish model and assaying for retinal and cerebellar integrity.Results: Exome sequencing revealed a complex heterozygous protein-truncating mutation in RP1L1, p.[(Lys111Glnfs*27; Gln2373*)], and a heterozygous nonsense mutation in C2orf71, p.(Ser512*). Mutations in both genes have previously been implicated in autosomal recessive non-syndromic RP, raising the possibility of a digenic model in this family. Functional testing in a zebrafish model for two key phenotypes of the affected person showed that the combinatorial suppression of rp1l1 and c2orf71l induced discrete pathology in terms of reduction of eye size with concomitant loss of rhodopsin in the photoreceptors, and disorganization of the cerebellum.Conclusions: We propose that the combination of heterozygous loss-of-function mutations in these genes drives syndromic retinal dystrophy, likely through the genetic interaction of at least two loci. Haploinsufficiency at each of these loci is insufficient to induce overt pathology.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Oftalmologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Ophthalmology (hsv//eng)
Nyckelord
- Cerebellum
- ciliopathy
- digenic inheritance
- hearing loss
- retinitis pigmentosa zebrafish
- Genetik
- Genetics
- Health and Medical Care Research
- Hälso- och sjukvårdsforskning
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Liu, Yangfan P.
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Bosch, Danielle ...
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Möller, Claes, 1 ...
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