LMX1B mutations cause hereditary FSGS without extrarenal involvement.

Area of Science:

• Genetics
• Nephrology
• Molecular Biology

Background:

• LMX1B is a transcription factor crucial for development.
• LMX1B mutations are known to cause nail-patella syndrome, a condition involving skeletal abnormalities and kidney disease (FSGS) with specific glomerular basement membrane (GBM) lesions.
• The spectrum of LMX1B-associated disease was not fully understood.

Purpose of the Study:

• To investigate the genetic cause of isolated autosomal dominant FSGS in a family without syndromic features.
• To determine if LMX1B mutations are implicated in FSGS cases lacking extrarenal manifestations or typical GBM abnormalities.
• To assess the frequency of LMX1B mutations in a broader cohort of unrelated FSGS families.

Main Methods:

• Linkage analysis and exome sequencing were employed to identify mutations in the affected family.
• Screening of additional unrelated families with FSGS was performed.
• In silico homology modeling of the LMX1B protein was used to predict the functional impact of identified mutations.

Main Results:

• An LMX1B mutation was identified in a family with autosomal dominant FSGS, notably without nail-patella syndrome features or characteristic GBM ultrastructural changes.
• Screening of 73 additional FSGS families revealed mutations in the same LMX1B amino acid residue (R246) in two other families.
• In silico analysis indicated that the identified mutations likely impair the interaction between the LMX1B homeodomain and DNA.

Conclusions:

• Isolated FSGS can result from mutations in genes typically associated with syndromic forms of the disease, such as LMX1B.
• The findings broaden the phenotypic spectrum of LMX1B mutations.
• These results underscore the importance of including LMX1B and other potentially involved genes in next-generation sequencing panels for diagnosing FSGS.