ARHGDIA: a novel gene implicated in nephrotic syndrome

Area of Science:

• Genetics
• Molecular Biology
• Nephrology

Background:

• Congenital nephrotic syndrome (CNS) is a severe kidney disorder caused by genetic defects in the glomerular filtration barrier.
• While known mutations account for most cases, up to 15% remain genetically unexplained.
• This study investigated two sisters with a suspected recessive form of CNS.

Observation:

• Whole exome sequencing identified shared mutations in five genes in the affected sisters.
• ARHGDIA, encoding Rho GDP dissociation inhibitor α (RhoGDIα), emerged as the prime candidate due to its known role in kidney function and mouse models.
• The sisters presented a homozygous deletion (c.553_555del(p.Asp185del)) in ARHGDIA, predicted to impair RhoGDIα's interaction with Rho GTPases.

Findings:

• The identified ARHGDIA mutation resulted in a non-functional RhoGDIα protein that could not bind to Rho GTPases (RhoA, Rac1, Cdc42).
• In kidney podocytes, RhoGDIα knockdown led to hyperactivation of Rho GTPases and impaired cell motility.
• Patient-derived fibroblasts showed mislocalized RhoGDIα, hyperactivated Rho GTPases, and reduced motility, confirming a loss-of-function mutation.

Implications:

• This research identifies ARHGDIA mutations as a novel cause of congenital nephrotic syndrome.
• Understanding the role of RhoGDIα in podocyte function is crucial for diagnosing and potentially treating heritable nephrotic syndromes.
• ARHGDIA should be included in genetic testing panels for unexplained congenital nephrotic syndrome cases.