A null founder variant in NPNT, encoding nephronectin, causes autosomal recessive renal agenesis

Area of Science:

• Genetics and Developmental Biology
• Nephrology
• Human Disease Pathogenesis

Background:

• Congenital anomalies of the kidney and urinary tract (CAKUT) encompass a range of developmental abnormalities.
• Bilateral renal agenesis (BRA) represents the most severe form of CAKUT.
• Previous studies in murine models implicated nephronectin (NPNT) and ITGA8 in kidney development and renal agenesis.

Purpose of the Study:

• To investigate the genetic basis of renal agenesis in two families with a history of BRA or unilateral renal agenesis.
• To confirm the role of NPNT in human renal agenesis.

Main Methods:

• Genome-wide linkage analysis was performed to identify genetic loci associated with BRA.
• Exome sequencing was utilized to detect variants within the identified linkage interval.
• Reverse transcription polymerase chain reaction (RT-PCR) was employed to assess transcript integrity and nonsense-mediated decay.

Main Results:

• Linkage analysis identified an autozygous locus linked to BRA at 4q24 in two families.
• Exome sequencing revealed a homozygous nonsense variant in the NPNT gene within the linkage region in both families.
• RT-PCR data confirmed complete nonsense-mediated decay of the NPNT transcript, indicating loss of function.

Conclusions:

• This study confirms NPNT as a candidate gene for human renal agenesis.
• The findings demonstrate that complete loss of NPNT function can be compatible with the development of a single kidney.