Exploring the Contribution of the Transporter AGT1/rBAT in Cystinuria Progression: Insights from Mouse Models and a Retrospective Cohort Study
More than 20 years have passed since the identification of <i>SLC3A1</i> and <i>SLC7A9</i> as causative genes for cystinuria. However, cystinuria patients exhibit significant variability in the age of lithiasis onset, recurrence, and response to treatment, suggesting the pres...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-12-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/24/17140 |
| _version_ | 1797380785803624448 |
|---|---|
| author | Clara Mayayo-Vallverdú Esther Prat Marta Vecino-Pérez Laura González Silvia Gràcia-Garcia Luz San Miguel Noelia Lopera Angela Arias Rafael Artuch Miguel López de Heredia Carlos Torrecilla Ferran Rousaud-Barón Oriol Angerri Ekaitz Errasti-Murugarren Virginia Nunes |
| author_facet | Clara Mayayo-Vallverdú Esther Prat Marta Vecino-Pérez Laura González Silvia Gràcia-Garcia Luz San Miguel Noelia Lopera Angela Arias Rafael Artuch Miguel López de Heredia Carlos Torrecilla Ferran Rousaud-Barón Oriol Angerri Ekaitz Errasti-Murugarren Virginia Nunes |
| author_sort | Clara Mayayo-Vallverdú |
| collection | DOAJ |
| description | More than 20 years have passed since the identification of <i>SLC3A1</i> and <i>SLC7A9</i> as causative genes for cystinuria. However, cystinuria patients exhibit significant variability in the age of lithiasis onset, recurrence, and response to treatment, suggesting the presence of modulatory factors influencing cystinuria severity. In 2016, a second renal cystine transporter, AGT1, encoded by the <i>SLC7A13</i> gene, was discovered. Although it was discarded as a causative gene for cystinuria, its possible effect as a modulatory gene remains unexplored. Thus, we analyzed its function in mouse models of cystinuria, screened the <i>SLC7A13</i> gene in 34 patients with different lithiasic phenotypes, and functionally characterized the identified variants. Mice results showed that AGT1/rBAT may have a protective role against cystine lithiasis. In addition, among the four missense variants detected in patients, two exhibited a 25% impairment in AGT1/rBAT transport. However, no correlation between <i>SLC7A13</i> genotypes and lithiasis phenotypes was observed in patients, probably because these variants were found in heterozygous states. In conclusion, our results, consistent with a previous study, suggest that AGT1/rBAT does not have a relevant effect on cystinuria patients, although an impact in patients carrying homozygous pathogenic variants cannot be discarded. |
| first_indexed | 2024-03-08T20:43:01Z |
| format | Article |
| id | doaj.art-b47f336ca4484d1d9c4d9ed53154c5bd |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T20:43:01Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b47f336ca4484d1d9c4d9ed53154c5bd2023-12-22T14:13:22ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0124241714010.3390/ijms242417140Exploring the Contribution of the Transporter AGT1/rBAT in Cystinuria Progression: Insights from Mouse Models and a Retrospective Cohort StudyClara Mayayo-Vallverdú0Esther Prat1Marta Vecino-Pérez2Laura González3Silvia Gràcia-Garcia4Luz San Miguel5Noelia Lopera6Angela Arias7Rafael Artuch8Miguel López de Heredia9Carlos Torrecilla10Ferran Rousaud-Barón11Oriol Angerri12Ekaitz Errasti-Murugarren13Virginia Nunes14Human Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), 08908 L’Hospitalet de Llobregat, SpainHuman Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), 08908 L’Hospitalet de Llobregat, SpainHuman Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), 08908 L’Hospitalet de Llobregat, SpainHuman Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), 08908 L’Hospitalet de Llobregat, SpainUrinary Lithiasis Laboratory, Fundació Puigvert, 08025 Barcelona, SpainUrology Service, Fundació Puigvert, 08025 Barcelona, SpainUrinary Lithiasis Laboratory, Fundació Puigvert, 08025 Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, SpainHuman Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), 08908 L’Hospitalet de Llobregat, SpainUrology Service, Hospital Universitari de Bellvitge, 08908 L’Hospitalet de Llobregat, SpainUrology Service, Fundació Puigvert, 08025 Barcelona, SpainUrology Service, Fundació Puigvert, 08025 Barcelona, SpainGenetics Section, Physiological Sciences Department, Health Sciences and Medicine Faculty, University of Barcelona, 08907 L’Hospitalet de Llobregat, SpainHuman Molecular Genetics Laboratory, Gene, Disease and Therapy Program, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), 08908 L’Hospitalet de Llobregat, SpainMore than 20 years have passed since the identification of <i>SLC3A1</i> and <i>SLC7A9</i> as causative genes for cystinuria. However, cystinuria patients exhibit significant variability in the age of lithiasis onset, recurrence, and response to treatment, suggesting the presence of modulatory factors influencing cystinuria severity. In 2016, a second renal cystine transporter, AGT1, encoded by the <i>SLC7A13</i> gene, was discovered. Although it was discarded as a causative gene for cystinuria, its possible effect as a modulatory gene remains unexplored. Thus, we analyzed its function in mouse models of cystinuria, screened the <i>SLC7A13</i> gene in 34 patients with different lithiasic phenotypes, and functionally characterized the identified variants. Mice results showed that AGT1/rBAT may have a protective role against cystine lithiasis. In addition, among the four missense variants detected in patients, two exhibited a 25% impairment in AGT1/rBAT transport. However, no correlation between <i>SLC7A13</i> genotypes and lithiasis phenotypes was observed in patients, probably because these variants were found in heterozygous states. In conclusion, our results, consistent with a previous study, suggest that AGT1/rBAT does not have a relevant effect on cystinuria patients, although an impact in patients carrying homozygous pathogenic variants cannot be discarded.https://www.mdpi.com/1422-0067/24/24/17140cystinuriacystine transporterrare disease<i>SLC7A13</i> variantsfunctional analysis |
| spellingShingle | Clara Mayayo-Vallverdú Esther Prat Marta Vecino-Pérez Laura González Silvia Gràcia-Garcia Luz San Miguel Noelia Lopera Angela Arias Rafael Artuch Miguel López de Heredia Carlos Torrecilla Ferran Rousaud-Barón Oriol Angerri Ekaitz Errasti-Murugarren Virginia Nunes Exploring the Contribution of the Transporter AGT1/rBAT in Cystinuria Progression: Insights from Mouse Models and a Retrospective Cohort Study International Journal of Molecular Sciences cystinuria cystine transporter rare disease <i>SLC7A13</i> variants functional analysis |
| title | Exploring the Contribution of the Transporter AGT1/rBAT in Cystinuria Progression: Insights from Mouse Models and a Retrospective Cohort Study |
| title_full | Exploring the Contribution of the Transporter AGT1/rBAT in Cystinuria Progression: Insights from Mouse Models and a Retrospective Cohort Study |
| title_fullStr | Exploring the Contribution of the Transporter AGT1/rBAT in Cystinuria Progression: Insights from Mouse Models and a Retrospective Cohort Study |
| title_full_unstemmed | Exploring the Contribution of the Transporter AGT1/rBAT in Cystinuria Progression: Insights from Mouse Models and a Retrospective Cohort Study |
| title_short | Exploring the Contribution of the Transporter AGT1/rBAT in Cystinuria Progression: Insights from Mouse Models and a Retrospective Cohort Study |
| title_sort | exploring the contribution of the transporter agt1 rbat in cystinuria progression insights from mouse models and a retrospective cohort study |
| topic | cystinuria cystine transporter rare disease <i>SLC7A13</i> variants functional analysis |
| url | https://www.mdpi.com/1422-0067/24/24/17140 |
| work_keys_str_mv | AT claramayayovallverdu exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT estherprat exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT martavecinoperez exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT lauragonzalez exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT silviagraciagarcia exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT luzsanmiguel exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT noelialopera exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT angelaarias exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT rafaelartuch exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT miguellopezdeheredia exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT carlostorrecilla exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT ferranrousaudbaron exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT oriolangerri exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT ekaitzerrastimurugarren exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy AT virginianunes exploringthecontributionofthetransporteragt1rbatincystinuriaprogressioninsightsfrommousemodelsandaretrospectivecohortstudy |