Pathogenicity of a Human Laminin β 2 Mutation Revealed in Models of Alport Syndrome

J Am Soc Nephrol. 2018 Mar;29(3):949-960. doi: 10.1681/ASN.2017090997. Epub 2017 Dec 20.

Abstract

Pierson syndrome is a congenital nephrotic syndrome with eye and neurologic defects caused by mutations in laminin β2 (LAMB2), a major component of the glomerular basement membrane (GBM). Pathogenic missense mutations in human LAMB2 cluster in or near the laminin amino-terminal (LN) domain, a domain required for extracellular polymerization of laminin trimers and basement membrane scaffolding. Here, we investigated an LN domain missense mutation, LAMB2-S80R, which was discovered in a patient with Pierson syndrome and unusually late onset of proteinuria. Biochemical data indicated that this mutation impairs laminin polymerization, which we hypothesized to be the cause of the patient's nephrotic syndrome. Testing this hypothesis in genetically altered mice showed that the corresponding amino acid change (LAMB2-S83R) alone is not pathogenic. However, expression of LAMB2-S83R significantly increased the rate of progression to kidney failure in a Col4a3-/- mouse model of autosomal recessive Alport syndrome and increased proteinuria in Col4a5+/- females that exhibit a mild form of X-linked Alport syndrome due to mosaic deposition of collagen α3α4α5(IV) in the GBM. Collectively, these data show the pathogenicity of LAMB2-S80R and provide the first evidence of genetic modification of Alport phenotypes by variation in another GBM component. This finding could help explain the wide range of Alport syndrome onset and severity observed in patients with Alport syndrome, even for family members who share the same COL4 mutation. Our results also show the complexities of using model organisms to investigate genetic variants suspected of being pathogenic in humans.

Keywords: Alport syndrome; glomerular basement membrane; laminin; nephrotic syndrome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Animals
  • Autoantigens / genetics
  • Collagen Type IV / genetics
  • Disease Models, Animal
  • Disease Progression
  • Eye Abnormalities / complications
  • Eye Abnormalities / genetics*
  • Female
  • Glomerular Basement Membrane / metabolism
  • Humans
  • Kidney Failure, Chronic / genetics*
  • Laminin / genetics*
  • Laminin / metabolism
  • Mice
  • Mice, Transgenic
  • Mutation, Missense
  • Myasthenic Syndromes, Congenital
  • Nephritis, Hereditary / genetics*
  • Nephritis, Hereditary / metabolism*
  • Nephritis, Hereditary / pathology
  • Nephrotic Syndrome / complications
  • Nephrotic Syndrome / genetics*
  • Phenotype
  • Polymerization
  • Proteinuria / genetics*
  • Pupil Disorders / complications
  • Pupil Disorders / genetics*

Substances

  • Autoantigens
  • Col4a5 protein, mouse
  • Collagen Type IV
  • Laminin
  • type IV collagen alpha3 chain
  • laminin beta2

Supplementary concepts

  • Pierson syndrome