June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
A missense mutation in SLC6A6 impairs taurine transport and results in Leber congenital amaurosis with short cardiac atrioventricular conduction time
Author Affiliations & Notes
  • Mukhtar Ullah
    Institute of Molecular and Clinical Ophthalmology Basel, Basel, Basel-Stadt, Switzerland
    Department of Ophthalmology, Universitat Basel, Basel, Basel-Stadt, Switzerland
  • Mathieu Quinodoz
    Institute of Molecular and Clinical Ophthalmology Basel, Basel, Basel-Stadt, Switzerland
    Department of Ophthalmology, Universitat Basel, Basel, Basel-Stadt, Switzerland
  • Atta Ur Rehman
    Department of Zoology, Faculty of Biological and Health Sciences, Hazara University, Mansehra, Pakistan
  • Madhur Shetty
    Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, United States
  • Rosalie Grijalva
    Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, United States
  • Giacomo Calzetti
    Institute of Molecular and Clinical Ophthalmology Basel, Basel, Basel-Stadt, Switzerland
    Department of Ophthalmology, Universitat Basel, Basel, Basel-Stadt, Switzerland
  • Abdur Rashid
    Government of Khyber Pakhtunkhwa Department of Higher Education Archives and Libraries, Peshawar, Khyber Pakhtunkhwa, Pakistan
  • Sanaullah Jan
    Hayatabad Medical Complex Department of Ophthalmology, Peshawar, Pakistan
    Khyber Girls Medical College, Peshawar, Pakistan
  • Alessandra Pia Porretta
    Service de cardiologie, Département cœur-vaisseaux, Centre Hospitalier Universitaire Vaudois, Lausanne, Vaud, Switzerland
    Department of Clinical-Surgical Diagnostic and Pediatric Sciences, Universita degli Studi di Pavia, Pavia, Lombardia, Italy
  • L. Keith Henry
    Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, United States
  • Andrea Superti-Furga
    Division of Genetic Medicine, Universite de Lausanne, Lausanne, Vaud, Switzerland
  • Carlo Rivolta
    Institute of Molecular and Clinical Ophthalmology Basel, Basel, Basel-Stadt, Switzerland
    Department of Ophthalmology, Universitat Basel, Basel, Basel-Stadt, Switzerland
  • Footnotes
    Commercial Relationships   Mukhtar Ullah None; Mathieu Quinodoz None; Atta Rehman None; Madhur Shetty None; Rosalie Grijalva None; Giacomo Calzetti None; Abdur Rashid None; Sanaullah Jan None; Alessandra Porretta None; L. Keith Henry None; Andrea Superti-Furga None; Carlo Rivolta None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4529. doi:
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      Mukhtar Ullah, Mathieu Quinodoz, Atta Ur Rehman, Madhur Shetty, Rosalie Grijalva, Giacomo Calzetti, Abdur Rashid, Sanaullah Jan, Alessandra Pia Porretta, L. Keith Henry, Andrea Superti-Furga, Carlo Rivolta; A missense mutation in SLC6A6 impairs taurine transport and results in Leber congenital amaurosis with short cardiac atrioventricular conduction time. Invest. Ophthalmol. Vis. Sci. 2023;64(8):4529.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Leber congenital amaurosis (LCA) is one of the most severe forms of inherited retinal dystrophy, accounting for 20% of childhood blindness. It is caused by mutations in ~30 different genes. In this work, we investigate the molecular pathology of a novel mutation in SLC6A6, the gene encoding the transporter of the amino acid taurine, in association with a syndromic form of LCA.

Methods : Ophthalmic diagnoses were achieved by detailed clinical examinations and electroretinography, whereas assessments of cardiac morphology and function were based on electrocardiography and echocardiography. Genetic analyses were performed by whole-exome and Sanger sequencing. SLC6A6 transporter function and membrane kinetics were evaluated by [3H] taurine uptake assays in HEK-293 cells transiently expressing native and mutant transporters. Assessment of taurine levels in plasma were performed by standard tests.

Results : A large family from the northwestern part of Pakistan was ascertained, including four affected siblings presenting with signs and symptoms typical of LCA and a short PR interval with narrow QRS on electrocardiogram. Echocardiography was normal. Exome and Sanger sequencing revealed a rare homozygous missense variant [NM_003043.5:c.746C>T, p.(Thr249Ile)] in SLC6A6 in all four patients, which co-segregated with disease in the family according to a recessive pattern of inheritance. Functional analysis of this mutation showed a significant 4-fold reduction in taurine transport, a 14-fold decrease in Vmax and a 2-fold decrease in Km, compared to the native SLC6A6, consistent with a kinetic deficit transporter function. Taurine levels in patients’ plasma were significantly decreased compared to heterozygous carriers, with mean values of 8.0 ± 2.8 µmol/L (n=4) and 37.7 ± 12.6 µmol/L (n=3), respectively.

Conclusions : We identify a novel missense variant in the SLC6A6 gene that significantly impacts taurine transport across the cell membrane and results in decreased plasma taurine, Leber congenital amaurosis, and changes in cardiac conduction.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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