Identification of new families and variants in autosomal dominant macular dystrophy associated with THRB
Abstract THRB encodes thyroid hormone receptor β which produces two human isoforms (TRβ1 and TRβ2) by alternative splicing. The first THRB variant associated with autosomal dominant macular dystrophy (ADMD), NM_001354712.2:c.283 + 1G > A, was recently described. This study aims to refine the opht...
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Nature Portfolio
2025-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-97768-9 |
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| author | Lidia Fernández-Caballero Fiona Blanco-Kelly Saoud Tahsin Swafiri María Inmaculada Martín-Mérida Mathieu Quinodoz Mukhtar Ullah Ester Carreño María Pilar Martin-Gutierrez Blanca García-Sandoval Pablo Minguez Carlo Rivolta Marta Corton Carmen Ayuso |
| author_facet | Lidia Fernández-Caballero Fiona Blanco-Kelly Saoud Tahsin Swafiri María Inmaculada Martín-Mérida Mathieu Quinodoz Mukhtar Ullah Ester Carreño María Pilar Martin-Gutierrez Blanca García-Sandoval Pablo Minguez Carlo Rivolta Marta Corton Carmen Ayuso |
| author_sort | Lidia Fernández-Caballero |
| collection | DOAJ |
| description | Abstract THRB encodes thyroid hormone receptor β which produces two human isoforms (TRβ1 and TRβ2) by alternative splicing. The first THRB variant associated with autosomal dominant macular dystrophy (ADMD), NM_001354712.2:c.283 + 1G > A, was recently described. This study aims to refine the ophthalmologic phenotype, report a novel THRB variant, and investigate the impact of these splicing variants at the protein level. THRB variants were identified by re-analysis of next-generation sequencing data from the FJD database. Family segregation was performed using Sanger sequencing. Clinical data were collected from self-reported ophthalmic history questionnaires and ophthalmic exams. Functional splicing test was performed by in vitro minigene approach. We identified 12 patients with ADMD from 3 families carrying variants in THRB. Two families carried the variant NM_001354712.2:c.283 + 1G > A, and one the novel variant NM_001354712.2:c.283G > A. Patients exhibited common ophthalmologic findings with disruption of subfoveal ellipsoid layers, and variable onset of symptoms. Splicing assays showed complete exon 5 skipping or a 6 bp deletion in both variants. Our results support the association of THRB with ADMD. The high intra-familial variability could be influenced by phenotype modifiers. Aberrant TRβ1/TRβ2 proteins could lead to a gain-of-function mechanism. Including THRB in inherited retinal dystrophy genetic panels could enhance diagnoses and clinical patient management. |
| format | Article |
| id | doaj-art-baef4c437bc7491391829cc945f6ba39 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-baef4c437bc7491391829cc945f6ba392025-08-20T03:52:20ZengNature PortfolioScientific Reports2045-23222025-04-0115111310.1038/s41598-025-97768-9Identification of new families and variants in autosomal dominant macular dystrophy associated with THRBLidia Fernández-Caballero0Fiona Blanco-Kelly1Saoud Tahsin Swafiri2María Inmaculada Martín-Mérida3Mathieu Quinodoz4Mukhtar Ullah5Ester Carreño6María Pilar Martin-Gutierrez7Blanca García-Sandoval8Pablo Minguez9Carlo Rivolta10Marta Corton11Carmen Ayuso12Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM)Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM)Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM)Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM)Institute of Molecular and Clinical Ophthalmology Basel (IOB)Institute of Molecular and Clinical Ophthalmology Basel (IOB)Department of Ophthalmology, Fundación Jiménez Díaz University HospitalDepartment of Ophthalmology, Fundación Jiménez Díaz University HospitalDepartment of Ophthalmology, Fundación Jiménez Díaz University HospitalDepartment of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM)Institute of Molecular and Clinical Ophthalmology Basel (IOB)Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM)Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM)Abstract THRB encodes thyroid hormone receptor β which produces two human isoforms (TRβ1 and TRβ2) by alternative splicing. The first THRB variant associated with autosomal dominant macular dystrophy (ADMD), NM_001354712.2:c.283 + 1G > A, was recently described. This study aims to refine the ophthalmologic phenotype, report a novel THRB variant, and investigate the impact of these splicing variants at the protein level. THRB variants were identified by re-analysis of next-generation sequencing data from the FJD database. Family segregation was performed using Sanger sequencing. Clinical data were collected from self-reported ophthalmic history questionnaires and ophthalmic exams. Functional splicing test was performed by in vitro minigene approach. We identified 12 patients with ADMD from 3 families carrying variants in THRB. Two families carried the variant NM_001354712.2:c.283 + 1G > A, and one the novel variant NM_001354712.2:c.283G > A. Patients exhibited common ophthalmologic findings with disruption of subfoveal ellipsoid layers, and variable onset of symptoms. Splicing assays showed complete exon 5 skipping or a 6 bp deletion in both variants. Our results support the association of THRB with ADMD. The high intra-familial variability could be influenced by phenotype modifiers. Aberrant TRβ1/TRβ2 proteins could lead to a gain-of-function mechanism. Including THRB in inherited retinal dystrophy genetic panels could enhance diagnoses and clinical patient management.https://doi.org/10.1038/s41598-025-97768-9 |
| spellingShingle | Lidia Fernández-Caballero Fiona Blanco-Kelly Saoud Tahsin Swafiri María Inmaculada Martín-Mérida Mathieu Quinodoz Mukhtar Ullah Ester Carreño María Pilar Martin-Gutierrez Blanca García-Sandoval Pablo Minguez Carlo Rivolta Marta Corton Carmen Ayuso Identification of new families and variants in autosomal dominant macular dystrophy associated with THRB Scientific Reports |
| title | Identification of new families and variants in autosomal dominant macular dystrophy associated with THRB |
| title_full | Identification of new families and variants in autosomal dominant macular dystrophy associated with THRB |
| title_fullStr | Identification of new families and variants in autosomal dominant macular dystrophy associated with THRB |
| title_full_unstemmed | Identification of new families and variants in autosomal dominant macular dystrophy associated with THRB |
| title_short | Identification of new families and variants in autosomal dominant macular dystrophy associated with THRB |
| title_sort | identification of new families and variants in autosomal dominant macular dystrophy associated with thrb |
| url | https://doi.org/10.1038/s41598-025-97768-9 |
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