Characterization of pre-mRNA Splicing Defects Caused by CLCN5 and OCRL Mutations and Identification of Novel Variants Associated with Dent Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. DNA Extraction, Amplification and Sequencing Analysis
2.3. In Silico Prediction Analysis and Criteria for Variant Selection
2.4. Amplification of CLCN5 and OCRL Genomic Fragments and Construction of Minigenes
2.5. Site-Direct Mutagenesis
2.6. Cell Culture, Transient Transfection and RT-PCR Assay
3. Results
3.1. Identification of Novel CLCN5 and OCRL Variants in Patients Diagnosed with Dent Disease
3.2. Selection of CLCN5 Missense Variant from Databases for Their Potential Effect on pre-mRNA Splicing
3.3. Functional Analysis of Variants
3.3.1. Minigene Analysis of CLCN5 Variants
Variants c.1535G>A, c.1537G>A and c.1641G>T Alter pre-mRNA Splicing of CLCN5
Variants in Exons 3, 7 and 9 of CLCN5 Did Not Alter pre-mRNA Splicing
3.3.2. Minigene Analysis of OCRL Variants
OCRL Variant c.1056+1G>A Results in the Skipping of Exon 11
OCRL Variant c.1467-1G>A Results in Incorporation of a Truncated Exon 15 in the mRNA
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Patient | Age 1 (Years) | LMWP | HC | NL/NC | Other Symptoms | Variant | Gene | Reference |
---|---|---|---|---|---|---|---|---|
P62 | 15 | + | + | + | − | c.952C>T; p.(R318C) | OCRL | [11] |
P422 | 3 | + | + | + | Hypotonia, ADD, GH deficit | c.1056+1G>A | OCRL | This study |
P508 | 3.5 | + | + | − | Developmental delay, congenital cataracts | c.2078C>T; p.(P693L) | OCRL | [62] |
P652 | 12 | + | + | − | − | c.1466G>A; p.(W489*) | CLCN5 | [63] |
P683 | 7 | + | + | + | − | c.1560_1561delTC; p.(L521Cfs*6) | CLCN5 | This study |
P749 | 0.8 | + | − | − | − | c.1537G>A; p.(G513R) | CLCN5 | [64] |
P801 | 6.5 | + | + | + | − | c.1641G>T; p.(W547C) | CLCN5 | This study |
P816 | 19 | + | + | − | − | c.976G>C; p.(G326R) | CLCN5 | This study |
P818 | 15 | + | + | − | − | c.1558_1559insT; p.(S520Ffs*8) | CLCN5 | [65] |
P841 | 2.7 | + | + | + | − | c.1467 − 1G>A | OCRL | This study |
P848 | 10.5 | + | + | − | − | c.966delC; p.(F322Lfs*37) | CLCN5 | This study |
P854 | 1.2 | + | − | − | Hyperaminoaciduria | c.2026delA; p.(T676Lfs*2) | CLCN5 | This study |
P921 | 0.8 | + | − | − | − | c.1600T>A; p.(Y534N) | CLCN5 | This study |
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Mura-Escorche, G.; Perdomo-Ramírez, A.; Ramos-Trujillo, E.; Trujillo-Frías, C.J.; Claverie-Martín, F., on behalf of the RenalTube Group. Characterization of pre-mRNA Splicing Defects Caused by CLCN5 and OCRL Mutations and Identification of Novel Variants Associated with Dent Disease. Biomedicines 2023, 11, 3082. https://doi.org/10.3390/biomedicines11113082
Mura-Escorche G, Perdomo-Ramírez A, Ramos-Trujillo E, Trujillo-Frías CJ, Claverie-Martín F on behalf of the RenalTube Group. Characterization of pre-mRNA Splicing Defects Caused by CLCN5 and OCRL Mutations and Identification of Novel Variants Associated with Dent Disease. Biomedicines. 2023; 11(11):3082. https://doi.org/10.3390/biomedicines11113082
Chicago/Turabian StyleMura-Escorche, Glorián, Ana Perdomo-Ramírez, Elena Ramos-Trujillo, Carmen Jane Trujillo-Frías, and Félix Claverie-Martín on behalf of the RenalTube Group. 2023. "Characterization of pre-mRNA Splicing Defects Caused by CLCN5 and OCRL Mutations and Identification of Novel Variants Associated with Dent Disease" Biomedicines 11, no. 11: 3082. https://doi.org/10.3390/biomedicines11113082