Characterising splicing defects of
The ATP-binding cassette subfamily A member 4 gene (ABCA4)-associated retinopathy, Stargardt disease, is the most common monogenic inherited retinal disease. Given the pathogenicity of numerous ABCA4 variants is yet to be examined and a significant proportion (more than 15%) of ABCA4 variants are ca...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Huang, Di [verfasserIn] Thompson, Jennifer A. [verfasserIn] Chen, Shang-Chih [verfasserIn] Adams, Abbie [verfasserIn] Pitout, Ianthe [verfasserIn] Lima, Alanis [verfasserIn] Zhang, Dan [verfasserIn] Jeffery, Rachael C. Heath [verfasserIn] Attia, Mary S. [verfasserIn] McLaren, Terri L. [verfasserIn] Lamey, Tina M. [verfasserIn] De Roach, John N. [verfasserIn] McLenachan, Samuel [verfasserIn] Aung-Htut, May Thandar [verfasserIn] Fletcher, Sue [verfasserIn] Wilton, Steve D. [verfasserIn] Chen, Fred K. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Experimental eye research - Amsterdam [u.a.] : Elsevier, 1962, 225 |
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| Übergeordnetes Werk: |
volume:225 |
| DOI / URN: |
10.1016/j.exer.2022.109276 |
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| Katalog-ID: |
ELV010403124 |
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| 520 | |a The ATP-binding cassette subfamily A member 4 gene (ABCA4)-associated retinopathy, Stargardt disease, is the most common monogenic inherited retinal disease. Given the pathogenicity of numerous ABCA4 variants is yet to be examined and a significant proportion (more than 15%) of ABCA4 variants are categorized as splice variants in silico, we therefore established a fibroblast-based splice assay to analyze ABCA4 variants in an Australian Stargardt disease cohort and characterize the pathogenic mechanisms of ABCA4 variants. A cohort of 67 patients clinically diagnosed with Stargardt disease was recruited. Genomic DNA was analysed using a commercial panel for ABCA4 variant detection and the consequences of ABCA4 variants were predicted in silico. Dermal fibroblasts were propagated from skin biopsies, total RNA was extracted and the ABCA4 transcript was amplified by RT-PCR. Our analysis identified a total of 67 unique alleles carrying 74 unique variants. The most prevalent splice-affecting complex allele c.[5461-10T>C; 5603A>T] was carried by 10% of patients in a compound heterozygous state. ABCA4 transcripts from exon 13 to exon 50 were readily detected in fibroblasts. In this region, aberrant splicing was evident in 10 out of 57 variant transcripts (18%), carried by 19 patients (28%). Patient-derived fibroblasts provide a feasible platform for identification of ABCA4 splice variants located within exons 13–50. Experimental evidence of aberrant splicing contributes to the pathogenic classification for ABCA4 variants. Moreover, identification of variants that affect splicing processes provides opportunities for intervention, in particular antisense oligonucleotide-mediated splice correction. | ||
| 650 | 4 | |a Stargardt disease | |
| 650 | 4 | |a Patient-derived fibroblasts | |
| 650 | 4 | |a Molecular analysis | |
| 700 | 1 | |a Thompson, Jennifer A. |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Shang-Chih |e verfasserin |4 aut | |
| 700 | 1 | |a Adams, Abbie |e verfasserin |4 aut | |
| 700 | 1 | |a Pitout, Ianthe |e verfasserin |4 aut | |
| 700 | 1 | |a Lima, Alanis |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Jeffery, Rachael C. Heath |e verfasserin |4 aut | |
| 700 | 1 | |a Attia, Mary S. |e verfasserin |4 aut | |
| 700 | 1 | |a McLaren, Terri L. |e verfasserin |4 aut | |
| 700 | 1 | |a Lamey, Tina M. |e verfasserin |4 aut | |
| 700 | 1 | |a De Roach, John N. |e verfasserin |4 aut | |
| 700 | 1 | |a McLenachan, Samuel |e verfasserin |4 aut | |
| 700 | 1 | |a Aung-Htut, May Thandar |e verfasserin |4 aut | |
| 700 | 1 | |a Fletcher, Sue |e verfasserin |4 aut | |
| 700 | 1 | |a Wilton, Steve D. |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Fred K. |e verfasserin |0 (orcid)0000-0003-2809-9930 |4 aut | |
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10.1016/j.exer.2022.109276 doi (DE-627)ELV010403124 (ELSEVIER)S0014-4835(22)00357-8 DE-627 ger DE-627 rda eng 610 VZ 44.95 bkl Huang, Di verfasserin aut Characterising splicing defects of 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The ATP-binding cassette subfamily A member 4 gene (ABCA4)-associated retinopathy, Stargardt disease, is the most common monogenic inherited retinal disease. Given the pathogenicity of numerous ABCA4 variants is yet to be examined and a significant proportion (more than 15%) of ABCA4 variants are categorized as splice variants in silico, we therefore established a fibroblast-based splice assay to analyze ABCA4 variants in an Australian Stargardt disease cohort and characterize the pathogenic mechanisms of ABCA4 variants. A cohort of 67 patients clinically diagnosed with Stargardt disease was recruited. Genomic DNA was analysed using a commercial panel for ABCA4 variant detection and the consequences of ABCA4 variants were predicted in silico. Dermal fibroblasts were propagated from skin biopsies, total RNA was extracted and the ABCA4 transcript was amplified by RT-PCR. Our analysis identified a total of 67 unique alleles carrying 74 unique variants. The most prevalent splice-affecting complex allele c.[5461-10T>C; 5603A>T] was carried by 10% of patients in a compound heterozygous state. ABCA4 transcripts from exon 13 to exon 50 were readily detected in fibroblasts. In this region, aberrant splicing was evident in 10 out of 57 variant transcripts (18%), carried by 19 patients (28%). Patient-derived fibroblasts provide a feasible platform for identification of ABCA4 splice variants located within exons 13–50. Experimental evidence of aberrant splicing contributes to the pathogenic classification for ABCA4 variants. Moreover, identification of variants that affect splicing processes provides opportunities for intervention, in particular antisense oligonucleotide-mediated splice correction. Stargardt disease Patient-derived fibroblasts Molecular analysis Thompson, Jennifer A. verfasserin aut Chen, Shang-Chih verfasserin aut Adams, Abbie verfasserin aut Pitout, Ianthe verfasserin aut Lima, Alanis verfasserin aut Zhang, Dan verfasserin aut Jeffery, Rachael C. Heath verfasserin aut Attia, Mary S. verfasserin aut McLaren, Terri L. verfasserin aut Lamey, Tina M. verfasserin aut De Roach, John N. verfasserin aut McLenachan, Samuel verfasserin aut Aung-Htut, May Thandar verfasserin aut Fletcher, Sue verfasserin aut Wilton, Steve D. verfasserin aut Chen, Fred K. verfasserin (orcid)0000-0003-2809-9930 aut Enthalten in Experimental eye research Amsterdam [u.a.] : Elsevier, 1962 225 Online-Ressource (DE-627)266018033 (DE-600)1466924-9 (DE-576)104193697 1096-0007 nnns volume:225 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.95 Augenheilkunde VZ AR 225 |
| spelling |
10.1016/j.exer.2022.109276 doi (DE-627)ELV010403124 (ELSEVIER)S0014-4835(22)00357-8 DE-627 ger DE-627 rda eng 610 VZ 44.95 bkl Huang, Di verfasserin aut Characterising splicing defects of 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The ATP-binding cassette subfamily A member 4 gene (ABCA4)-associated retinopathy, Stargardt disease, is the most common monogenic inherited retinal disease. Given the pathogenicity of numerous ABCA4 variants is yet to be examined and a significant proportion (more than 15%) of ABCA4 variants are categorized as splice variants in silico, we therefore established a fibroblast-based splice assay to analyze ABCA4 variants in an Australian Stargardt disease cohort and characterize the pathogenic mechanisms of ABCA4 variants. A cohort of 67 patients clinically diagnosed with Stargardt disease was recruited. Genomic DNA was analysed using a commercial panel for ABCA4 variant detection and the consequences of ABCA4 variants were predicted in silico. Dermal fibroblasts were propagated from skin biopsies, total RNA was extracted and the ABCA4 transcript was amplified by RT-PCR. Our analysis identified a total of 67 unique alleles carrying 74 unique variants. The most prevalent splice-affecting complex allele c.[5461-10T>C; 5603A>T] was carried by 10% of patients in a compound heterozygous state. ABCA4 transcripts from exon 13 to exon 50 were readily detected in fibroblasts. In this region, aberrant splicing was evident in 10 out of 57 variant transcripts (18%), carried by 19 patients (28%). Patient-derived fibroblasts provide a feasible platform for identification of ABCA4 splice variants located within exons 13–50. Experimental evidence of aberrant splicing contributes to the pathogenic classification for ABCA4 variants. Moreover, identification of variants that affect splicing processes provides opportunities for intervention, in particular antisense oligonucleotide-mediated splice correction. Stargardt disease Patient-derived fibroblasts Molecular analysis Thompson, Jennifer A. verfasserin aut Chen, Shang-Chih verfasserin aut Adams, Abbie verfasserin aut Pitout, Ianthe verfasserin aut Lima, Alanis verfasserin aut Zhang, Dan verfasserin aut Jeffery, Rachael C. Heath verfasserin aut Attia, Mary S. verfasserin aut McLaren, Terri L. verfasserin aut Lamey, Tina M. verfasserin aut De Roach, John N. verfasserin aut McLenachan, Samuel verfasserin aut Aung-Htut, May Thandar verfasserin aut Fletcher, Sue verfasserin aut Wilton, Steve D. verfasserin aut Chen, Fred K. verfasserin (orcid)0000-0003-2809-9930 aut Enthalten in Experimental eye research Amsterdam [u.a.] : Elsevier, 1962 225 Online-Ressource (DE-627)266018033 (DE-600)1466924-9 (DE-576)104193697 1096-0007 nnns volume:225 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.95 Augenheilkunde VZ AR 225 |
| allfields_unstemmed |
10.1016/j.exer.2022.109276 doi (DE-627)ELV010403124 (ELSEVIER)S0014-4835(22)00357-8 DE-627 ger DE-627 rda eng 610 VZ 44.95 bkl Huang, Di verfasserin aut Characterising splicing defects of 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The ATP-binding cassette subfamily A member 4 gene (ABCA4)-associated retinopathy, Stargardt disease, is the most common monogenic inherited retinal disease. Given the pathogenicity of numerous ABCA4 variants is yet to be examined and a significant proportion (more than 15%) of ABCA4 variants are categorized as splice variants in silico, we therefore established a fibroblast-based splice assay to analyze ABCA4 variants in an Australian Stargardt disease cohort and characterize the pathogenic mechanisms of ABCA4 variants. A cohort of 67 patients clinically diagnosed with Stargardt disease was recruited. Genomic DNA was analysed using a commercial panel for ABCA4 variant detection and the consequences of ABCA4 variants were predicted in silico. Dermal fibroblasts were propagated from skin biopsies, total RNA was extracted and the ABCA4 transcript was amplified by RT-PCR. Our analysis identified a total of 67 unique alleles carrying 74 unique variants. The most prevalent splice-affecting complex allele c.[5461-10T>C; 5603A>T] was carried by 10% of patients in a compound heterozygous state. ABCA4 transcripts from exon 13 to exon 50 were readily detected in fibroblasts. In this region, aberrant splicing was evident in 10 out of 57 variant transcripts (18%), carried by 19 patients (28%). Patient-derived fibroblasts provide a feasible platform for identification of ABCA4 splice variants located within exons 13–50. Experimental evidence of aberrant splicing contributes to the pathogenic classification for ABCA4 variants. Moreover, identification of variants that affect splicing processes provides opportunities for intervention, in particular antisense oligonucleotide-mediated splice correction. Stargardt disease Patient-derived fibroblasts Molecular analysis Thompson, Jennifer A. verfasserin aut Chen, Shang-Chih verfasserin aut Adams, Abbie verfasserin aut Pitout, Ianthe verfasserin aut Lima, Alanis verfasserin aut Zhang, Dan verfasserin aut Jeffery, Rachael C. Heath verfasserin aut Attia, Mary S. verfasserin aut McLaren, Terri L. verfasserin aut Lamey, Tina M. verfasserin aut De Roach, John N. verfasserin aut McLenachan, Samuel verfasserin aut Aung-Htut, May Thandar verfasserin aut Fletcher, Sue verfasserin aut Wilton, Steve D. verfasserin aut Chen, Fred K. verfasserin (orcid)0000-0003-2809-9930 aut Enthalten in Experimental eye research Amsterdam [u.a.] : Elsevier, 1962 225 Online-Ressource (DE-627)266018033 (DE-600)1466924-9 (DE-576)104193697 1096-0007 nnns volume:225 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.95 Augenheilkunde VZ AR 225 |
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10.1016/j.exer.2022.109276 doi (DE-627)ELV010403124 (ELSEVIER)S0014-4835(22)00357-8 DE-627 ger DE-627 rda eng 610 VZ 44.95 bkl Huang, Di verfasserin aut Characterising splicing defects of 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The ATP-binding cassette subfamily A member 4 gene (ABCA4)-associated retinopathy, Stargardt disease, is the most common monogenic inherited retinal disease. Given the pathogenicity of numerous ABCA4 variants is yet to be examined and a significant proportion (more than 15%) of ABCA4 variants are categorized as splice variants in silico, we therefore established a fibroblast-based splice assay to analyze ABCA4 variants in an Australian Stargardt disease cohort and characterize the pathogenic mechanisms of ABCA4 variants. A cohort of 67 patients clinically diagnosed with Stargardt disease was recruited. Genomic DNA was analysed using a commercial panel for ABCA4 variant detection and the consequences of ABCA4 variants were predicted in silico. Dermal fibroblasts were propagated from skin biopsies, total RNA was extracted and the ABCA4 transcript was amplified by RT-PCR. Our analysis identified a total of 67 unique alleles carrying 74 unique variants. The most prevalent splice-affecting complex allele c.[5461-10T>C; 5603A>T] was carried by 10% of patients in a compound heterozygous state. ABCA4 transcripts from exon 13 to exon 50 were readily detected in fibroblasts. In this region, aberrant splicing was evident in 10 out of 57 variant transcripts (18%), carried by 19 patients (28%). Patient-derived fibroblasts provide a feasible platform for identification of ABCA4 splice variants located within exons 13–50. Experimental evidence of aberrant splicing contributes to the pathogenic classification for ABCA4 variants. Moreover, identification of variants that affect splicing processes provides opportunities for intervention, in particular antisense oligonucleotide-mediated splice correction. Stargardt disease Patient-derived fibroblasts Molecular analysis Thompson, Jennifer A. verfasserin aut Chen, Shang-Chih verfasserin aut Adams, Abbie verfasserin aut Pitout, Ianthe verfasserin aut Lima, Alanis verfasserin aut Zhang, Dan verfasserin aut Jeffery, Rachael C. Heath verfasserin aut Attia, Mary S. verfasserin aut McLaren, Terri L. verfasserin aut Lamey, Tina M. verfasserin aut De Roach, John N. verfasserin aut McLenachan, Samuel verfasserin aut Aung-Htut, May Thandar verfasserin aut Fletcher, Sue verfasserin aut Wilton, Steve D. verfasserin aut Chen, Fred K. verfasserin (orcid)0000-0003-2809-9930 aut Enthalten in Experimental eye research Amsterdam [u.a.] : Elsevier, 1962 225 Online-Ressource (DE-627)266018033 (DE-600)1466924-9 (DE-576)104193697 1096-0007 nnns volume:225 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.95 Augenheilkunde VZ AR 225 |
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10.1016/j.exer.2022.109276 doi (DE-627)ELV010403124 (ELSEVIER)S0014-4835(22)00357-8 DE-627 ger DE-627 rda eng 610 VZ 44.95 bkl Huang, Di verfasserin aut Characterising splicing defects of 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The ATP-binding cassette subfamily A member 4 gene (ABCA4)-associated retinopathy, Stargardt disease, is the most common monogenic inherited retinal disease. Given the pathogenicity of numerous ABCA4 variants is yet to be examined and a significant proportion (more than 15%) of ABCA4 variants are categorized as splice variants in silico, we therefore established a fibroblast-based splice assay to analyze ABCA4 variants in an Australian Stargardt disease cohort and characterize the pathogenic mechanisms of ABCA4 variants. A cohort of 67 patients clinically diagnosed with Stargardt disease was recruited. Genomic DNA was analysed using a commercial panel for ABCA4 variant detection and the consequences of ABCA4 variants were predicted in silico. Dermal fibroblasts were propagated from skin biopsies, total RNA was extracted and the ABCA4 transcript was amplified by RT-PCR. Our analysis identified a total of 67 unique alleles carrying 74 unique variants. The most prevalent splice-affecting complex allele c.[5461-10T>C; 5603A>T] was carried by 10% of patients in a compound heterozygous state. ABCA4 transcripts from exon 13 to exon 50 were readily detected in fibroblasts. In this region, aberrant splicing was evident in 10 out of 57 variant transcripts (18%), carried by 19 patients (28%). Patient-derived fibroblasts provide a feasible platform for identification of ABCA4 splice variants located within exons 13–50. Experimental evidence of aberrant splicing contributes to the pathogenic classification for ABCA4 variants. Moreover, identification of variants that affect splicing processes provides opportunities for intervention, in particular antisense oligonucleotide-mediated splice correction. Stargardt disease Patient-derived fibroblasts Molecular analysis Thompson, Jennifer A. verfasserin aut Chen, Shang-Chih verfasserin aut Adams, Abbie verfasserin aut Pitout, Ianthe verfasserin aut Lima, Alanis verfasserin aut Zhang, Dan verfasserin aut Jeffery, Rachael C. Heath verfasserin aut Attia, Mary S. verfasserin aut McLaren, Terri L. verfasserin aut Lamey, Tina M. verfasserin aut De Roach, John N. verfasserin aut McLenachan, Samuel verfasserin aut Aung-Htut, May Thandar verfasserin aut Fletcher, Sue verfasserin aut Wilton, Steve D. verfasserin aut Chen, Fred K. verfasserin (orcid)0000-0003-2809-9930 aut Enthalten in Experimental eye research Amsterdam [u.a.] : Elsevier, 1962 225 Online-Ressource (DE-627)266018033 (DE-600)1466924-9 (DE-576)104193697 1096-0007 nnns volume:225 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.95 Augenheilkunde VZ AR 225 |
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Huang, Di @@aut@@ Thompson, Jennifer A. @@aut@@ Chen, Shang-Chih @@aut@@ Adams, Abbie @@aut@@ Pitout, Ianthe @@aut@@ Lima, Alanis @@aut@@ Zhang, Dan @@aut@@ Jeffery, Rachael C. Heath @@aut@@ Attia, Mary S. @@aut@@ McLaren, Terri L. @@aut@@ Lamey, Tina M. @@aut@@ De Roach, John N. @@aut@@ McLenachan, Samuel @@aut@@ Aung-Htut, May Thandar @@aut@@ Fletcher, Sue @@aut@@ Wilton, Steve D. @@aut@@ Chen, Fred K. @@aut@@ |
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2022-01-01T00:00:00Z |
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Huang, Di Thompson, Jennifer A. Chen, Shang-Chih Adams, Abbie Pitout, Ianthe Lima, Alanis Zhang, Dan Jeffery, Rachael C. Heath Attia, Mary S. McLaren, Terri L. Lamey, Tina M. De Roach, John N. McLenachan, Samuel Aung-Htut, May Thandar Fletcher, Sue Wilton, Steve D. Chen, Fred K. |
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characterising splicing defects of |
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The ATP-binding cassette subfamily A member 4 gene (ABCA4)-associated retinopathy, Stargardt disease, is the most common monogenic inherited retinal disease. Given the pathogenicity of numerous ABCA4 variants is yet to be examined and a significant proportion (more than 15%) of ABCA4 variants are categorized as splice variants in silico, we therefore established a fibroblast-based splice assay to analyze ABCA4 variants in an Australian Stargardt disease cohort and characterize the pathogenic mechanisms of ABCA4 variants. A cohort of 67 patients clinically diagnosed with Stargardt disease was recruited. Genomic DNA was analysed using a commercial panel for ABCA4 variant detection and the consequences of ABCA4 variants were predicted in silico. Dermal fibroblasts were propagated from skin biopsies, total RNA was extracted and the ABCA4 transcript was amplified by RT-PCR. Our analysis identified a total of 67 unique alleles carrying 74 unique variants. The most prevalent splice-affecting complex allele c.[5461-10T>C; 5603A>T] was carried by 10% of patients in a compound heterozygous state. ABCA4 transcripts from exon 13 to exon 50 were readily detected in fibroblasts. In this region, aberrant splicing was evident in 10 out of 57 variant transcripts (18%), carried by 19 patients (28%). Patient-derived fibroblasts provide a feasible platform for identification of ABCA4 splice variants located within exons 13–50. Experimental evidence of aberrant splicing contributes to the pathogenic classification for ABCA4 variants. Moreover, identification of variants that affect splicing processes provides opportunities for intervention, in particular antisense oligonucleotide-mediated splice correction. |
| abstractGer |
The ATP-binding cassette subfamily A member 4 gene (ABCA4)-associated retinopathy, Stargardt disease, is the most common monogenic inherited retinal disease. Given the pathogenicity of numerous ABCA4 variants is yet to be examined and a significant proportion (more than 15%) of ABCA4 variants are categorized as splice variants in silico, we therefore established a fibroblast-based splice assay to analyze ABCA4 variants in an Australian Stargardt disease cohort and characterize the pathogenic mechanisms of ABCA4 variants. A cohort of 67 patients clinically diagnosed with Stargardt disease was recruited. Genomic DNA was analysed using a commercial panel for ABCA4 variant detection and the consequences of ABCA4 variants were predicted in silico. Dermal fibroblasts were propagated from skin biopsies, total RNA was extracted and the ABCA4 transcript was amplified by RT-PCR. Our analysis identified a total of 67 unique alleles carrying 74 unique variants. The most prevalent splice-affecting complex allele c.[5461-10T>C; 5603A>T] was carried by 10% of patients in a compound heterozygous state. ABCA4 transcripts from exon 13 to exon 50 were readily detected in fibroblasts. In this region, aberrant splicing was evident in 10 out of 57 variant transcripts (18%), carried by 19 patients (28%). Patient-derived fibroblasts provide a feasible platform for identification of ABCA4 splice variants located within exons 13–50. Experimental evidence of aberrant splicing contributes to the pathogenic classification for ABCA4 variants. Moreover, identification of variants that affect splicing processes provides opportunities for intervention, in particular antisense oligonucleotide-mediated splice correction. |
| abstract_unstemmed |
The ATP-binding cassette subfamily A member 4 gene (ABCA4)-associated retinopathy, Stargardt disease, is the most common monogenic inherited retinal disease. Given the pathogenicity of numerous ABCA4 variants is yet to be examined and a significant proportion (more than 15%) of ABCA4 variants are categorized as splice variants in silico, we therefore established a fibroblast-based splice assay to analyze ABCA4 variants in an Australian Stargardt disease cohort and characterize the pathogenic mechanisms of ABCA4 variants. A cohort of 67 patients clinically diagnosed with Stargardt disease was recruited. Genomic DNA was analysed using a commercial panel for ABCA4 variant detection and the consequences of ABCA4 variants were predicted in silico. Dermal fibroblasts were propagated from skin biopsies, total RNA was extracted and the ABCA4 transcript was amplified by RT-PCR. Our analysis identified a total of 67 unique alleles carrying 74 unique variants. The most prevalent splice-affecting complex allele c.[5461-10T>C; 5603A>T] was carried by 10% of patients in a compound heterozygous state. ABCA4 transcripts from exon 13 to exon 50 were readily detected in fibroblasts. In this region, aberrant splicing was evident in 10 out of 57 variant transcripts (18%), carried by 19 patients (28%). Patient-derived fibroblasts provide a feasible platform for identification of ABCA4 splice variants located within exons 13–50. Experimental evidence of aberrant splicing contributes to the pathogenic classification for ABCA4 variants. Moreover, identification of variants that affect splicing processes provides opportunities for intervention, in particular antisense oligonucleotide-mediated splice correction. |
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| score |
7.400403 |