Taurine treatment of retinal degeneration and cardiomyopathy in a consanguineous family with SLC6A6 taurine transporter deficiency

Abstract

In a consanguineous Pakistani family with two affected individuals, a homozygous variant Gly399Val in the eighth transmembrane domain of the taurine transporter SLC6A6 was identified resulting in a hypomorph transporting capacity of ~15% compared with normal. Three-dimensional modeling of this variant has indicated that it likely causes displacement of the Tyr138 (TM3) side chain, important for transport of taurine. The affected individuals presented with rapidly progressive childhood retinal degeneration, cardiomyopathy and almost undetectable plasma taurine levels. Oral taurine supplementation of 100 mg/kg/day resulted in maintenance of normal blood taurine levels. Following approval by the ethics committee, a long-term supplementation treatment was introduced. Remarkably, after 24-months, the cardiomyopathy was corrected in both affected siblings, and in the 6-years-old, the retinal degeneration was arrested, and the vision was clinically improved. Similar therapeutic approaches could be employed in Mendelian phenotypes caused by the dysfunction of the hundreds of other molecular transporters.

Figure 1

The segregation, conservation and 3D modeling of the SLC6A6 pathogenic variant Gly399Val in family F315. (A) Pedigree of consanguineous family F315 showing the segregation of the homozygous pathogenic variant NM_003043.5:c.1196G > T:p.(Gly399Val) in the SLC6A6 gene. (B) Chromatograms of Sanger sequencing showing the segregation of the SLC6A6 variant c.1196G > T:p.(Gly399Val) in all family members tested. (C) Amino acid alignment in various species showing that Gly399 is well conserved. (D) Molecular modeling of the SLC6A6 variant Gly399Val indicating that Val399 is predicted to cause the displacement of the Tyr138 (TM3) side chain, which is important for recognition and transport of the ligand.

Figure 2

Functional characterization of SLC6A6 activity from patient-derived fibroblasts. (A) Specific taurine saturation uptake analysis in patient-derived fibroblasts. Fibroblasts of affected individuals IV:1 (filled circle), IV:3(open circle) and parents III:3 (closed square) and III:4 (open square) were incubated with [³H] taurine concentrations from 0.05 to 250 μM for 10 min. Non-specific counts were determined by inhibition of SLC6A6 with β-alanine (25 mM) and subtracted from total counts. (B) Western Blot detection of SLC6A6 in the plasma membrane from patient-derived fibroblasts. Surface protein was purified through biotinylation with a cell impermeant crosslinker and detected using anti-SLC6A6 antibody. (C) Percent surface expression was calculated from band densitometry for each sample and normalized to TFRC and plotted. ^*P < 0.05.

Figure 3

Results of taurine supplementation therapy for 24-months. (A) Taurine levels in the blood of both affected individuals (IV:1 and IV:3) before and after 6-months, 1-year and 2-years of taurine supplementation. (B) Results of the echocardiography show that the cardiomyopathy of both affected individuals (IV:1 and IV:3) has been corrected after 2-years of taurine supplementation. LVESD: left ventricular end-systolic diameter, LVEDD: left ventricular end diastolic diameter, EF: ejection fraction, FS: fractional shortening. Green and red numbers represent normal and abnormal values respectively. (C, D) Fundus photographs and macular OCT of the right eye (C) and left eye (D) of the patient IV:3 at baseline and after 24 months of taurine supplementation; anatomical stability with preservation of foveal photoreceptors can be noted.