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<p><i>THRB</i> encodes thyroid hormone receptor β which produces two human isoforms (TRβ1 and TRβ2) by alternative splicing. The first <i>THRB</i> variant associated with autosomal dominant macular dystrophy (ADMD), NM_001354712.2:c.283 + 1G &gt; A, was recently described. This study aims to refine the ophthalmologic phenotype, report a novel <i>THRB</i> variant, and investigate the impact of these splicing variants at the protein level. <i>THRB</i> 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 <i>THRB</i>. Two families carried the variant NM_001354712.2:c.283 + 1G &gt; A, and one the novel variant NM_001354712.2:c.283G &gt; 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&#xa0;bp deletion in both variants. Our results support the association of <i>THRB</i> 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 <i>THRB</i> in inherited retinal dystrophy genetic panels could enhance diagnoses and clinical patient management.</p>

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Identification of new families and variants in autosomal dominant macular dystrophy associated with THRB

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月28日

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  • 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

摘要

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.