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Kidney Week

Abstract: FR-PO1009

Recessive Mutations of LAMA3 Cause Nephrotic Syndrome

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Mao, Youying, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Ashraf, Shazia, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Mann, Nina, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Nakayama, Makiko, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Kolvenbach, Caroline M., Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Schneider, Ronen, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Majmundar, Amar J., Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background

Integrin α3β1 represents the major podocyte integrin heterodimer. Itga3 knock out mice have severe defects in podocyte growth and differentiation, and in glomerular basement membrane organization (Kreidberg Development 122:3537, 1996), and ITGB4 mutation causes nephrotic syndrome (NS) in humans. In the glomerular basement membrane, integrin α3β1 is the main receptor for laminins, which are heterotrimers composed of laminin subunits α5 (LAMA5) or subunits α3 (LAMA3), β2 (LAMB2) and g1 (LAMC1). Monogenic mutations in two laminin genes have been identified to cause NS in humans, including LAMA5 (Braun NDT, in press 2018) and LAMB2 (Zenker Hum Mol Genet 13: 2625, 2004). In additional LAMA3 knock out mice have abnormal glomerulogenesis (Abrass KI 70:1062, 2006).

Methods

To identify additional monogenic causes of NS, we performed whole exome sequencing in a cohort of 600 families with pediatric NS under a recessive model.

Results

In 3 families, in whom mutation in the 55 known monogenic genes of NS were excluded, we identified 3 different homozygous mutations in the gene LAMA3 as likely causative for NS. In family B149 with congenital NS, we detected the mutation p.S1359A (homozygous, conserved to X.tropicalis). In A2069 2 siblings with steroid dependent NS, we detected the mutation p.T2527I (homozygous, conserved to G.gallus). In A2563 with steroid sensitive NS, we detected homozygous truncation mutation p.E1354*.

Conclusion

We here identified LAMA3 as a new candidate gene for pediatric NS.

Funding

  • Other NIH Support