SLC6A6 and Dilated Cardiomyopathy

The association between SLC6A6 and dilated cardiomyopathy is supported by multiple lines of evidence, including robust genetic findings and concordant functional studies. A homozygous splice site deletion in SLC6A6 was identified in at least one patient with dilated cardiomyopathy (PMID:29886034), and this finding is bolstered by a large genome‑wide association study comprising 2719 cases that nominated SLC6A6 as the most likely candidate at the 3p25.1 locus (PMID:33677556).

The genetic evidence indicates an autosomal recessive inheritance model, with deleterious variants such as loss‐of‐function and splice site changes contributing to the disease phenotype. In addition, detailed in silico analyses and functional annotations from multi‑patient cohorts have confirmed the gene burden and pathogenic potential of SLC6A6 in the context of dilated cardiomyopathy (PMID:29886034, PMID:33677556).

At the molecular level, a reported variant, c.233C>A (p.Ala78Glu), exemplifies a deleterious missense change associated with impaired taurine transport. This specific variant, derived from studies on TAUT function in related disorders, underscores the plausible mechanistic link between altered transporter function and cardiac dysfunction (PMID:31345061).

Functional studies further support the clinical association. In vitro assays in cardiac-inspired cellular systems and complementary animal models have revealed that reduced taurine uptake, due to altered SLC6A6 activity, correlates with myocardial dysfunction. Additionally, studies assessing the regulation of the taurine transporter by transcription factors have provided mechanistic insights that align with the phenotype observed in dilated cardiomyopathy (PMID:12681485, PMID:37561545).

Despite the complex genetic architecture of dilated cardiomyopathy, no significant conflicting evidence has been reported that disputes the role of SLC6A6. The convergent genetic signals from both case‑based sequencing and large cohort analyses, along with consistent functional data, consolidate the gene‑disease relationship.

In conclusion, the integration of multi‑cohort genetic findings and supportive functional studies underlines a strong gene‑disease association between SLC6A6 and dilated cardiomyopathy. This robust evidence base facilitates diagnostic decision‑making and holds promise for informing targeted therapeutic interventions.

References

• Gene • 2018 • Rare genetic mutations in Pakistani patients with dilated cardiomyopathy PMID:29886034
• European heart journal • 2021 • Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23 PMID:33677556
• FEBS letters • 2003 • Regulation of taurine transporter gene (TauT) by WT1 PMID:12681485
• FASEB journal • 2019 • Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration PMID:31345061
• FASEB journal • 2023 • Deficiency of Pdk1 drives heart failure by impairing taurine homeostasis through Slc6a6 PMID:37561545

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