A missense variant in SLC12A3 gene enhances aberrant splicing causing Gitelman syndrome

Area of Science:

• Genetics
• Molecular Biology
• Nephrology

Background:

• Gitelman syndrome (GS) is the most common genetic tubulopathy, characterized by electrolyte imbalances due to mutations in the SLC12A3 gene.
• The syndrome typically presents with hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis.

Observation:

• A case of GS was identified in an asymptomatic woman with incidental hypokalemia during antenatal screening.
• Genetic analysis revealed two heterozygous SLC12A3 variants: c.625C>T (p.Arg209Trp, a known loss-of-function) and c.965C>T (p.Ala322Val).

Findings:

• The c.965C>T variant was found to generate two distinct cDNA transcripts.
• One transcript contains the p.Ala322Val missense mutation, while the other exhibits an in-frame deletion of exons 7 and 8, potentially disrupting chloride transport.
• This variant influences splicing, affecting the transcription of an upstream exon (exon 7) from exon 8.

Implications:

• This research elucidates novel mechanisms of splicing alterations in Gitelman syndrome.
• Understanding these intricate splicing events is crucial for accurate genetic diagnosis and potential therapeutic strategies for GS.
• The findings highlight the complex genetic underpinnings of tubulopathies and the importance of detailed molecular analysis.