TY - JOUR
T1 - Pathogenicity of a human laminin β2 mutation revealed in models of alport syndrome
AU - Funk, Steven D.
AU - Bayer, Raymond H.
AU - Malone, Andrew F.
AU - McKee, Karen K.
AU - Yurchenco, Peter D.
AU - Miner, Jeffrey H.
N1 - Funding Information:
S.D.F. was supported by NIH grant T32DK007126. This work was funded by NIH grants R01DK036425 (to P.D.Y.) and R01DK078314 (to J.H.M.). Production of transgenic and knock-in mice was supported by Diabetes Research Center Transgenic and Embryonic Stem Cell Core grant P30DK020579 and Digestive Diseases Research Core Center Murine Models Core grant P30DK052574.
Funding Information:
We thank Gloriosa Go and Jennifer Richardson for technical assistance, the Transgenic Vectors Core for design and validation of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 guideA, the Mouse Genetics Core for nucleic acid microinjections and mouse husbandry, the Pulmonary Morphology Core and Advanced Imaging and Tissue Analysis Core (supported by National Institutes of Health [NIH] grant P30DK052574) for histology, and the Washington University Center for Cellular Imaging for electron microscopy. We are grateful to Takako Sasaki, Yoshikazu Sado, and Dorin-Bogdan Borza for gifts of antibodies. S.D.F. was supported by NIH grant T32DK007126. This work was funded by NIH grants R01DK036425 (to P.D.Y.) and R01DK078314 (to J.H.M.). Production of transgenic and knock-in mice was supported by Diabetes Research Center Transgenic and Embryonic Stem Cell Core grant P30DK020579 and Digestive Diseases Research Core Center Murine Models Core grant P30DK052574.
Funding Information:
We thank Gloriosa Go and Jennifer Richardson for technical assistance, the Transgenic Vectors Core for design and validation of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 guideA, the Mouse Genetics Core for nucleic acid microinjections and mouse husbandry, the Pulmonary Morphology Core and Advanced Imaging and Tissue Analysis Core (supported by National Institutes of Health [NIH] grant P30DK052574) for histology, and the Washington University Center for Cellular Imaging for electron microscopy. We are grateful to Takako Sasaki, Yoshikazu Sado, and Dorin-Bogdan Borza for gifts of antibodies.
Publisher Copyright:
Copyright © 2018 by the American Society of Nephrology.
PY - 2018/3
Y1 - 2018/3
N2 - Pierson syndrome is a congenital nephrotic syndromewith eye and neurologic defects caused bymutations in laminin β2 (LAMB2), amajor 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 -/- mousemodel of autosomal recessive Alport syndrome and increased proteinuria in Col4a5 +/- females that exhibit amild formof X-linked Alport syndrome due tomosaic deposition of collagen a3a4a5(IV) in theGBM. Collectively, these data showthe 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.
AB - Pierson syndrome is a congenital nephrotic syndromewith eye and neurologic defects caused bymutations in laminin β2 (LAMB2), amajor 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 -/- mousemodel of autosomal recessive Alport syndrome and increased proteinuria in Col4a5 +/- females that exhibit amild formof X-linked Alport syndrome due tomosaic deposition of collagen a3a4a5(IV) in theGBM. Collectively, these data showthe 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.
UR - http://www.scopus.com/inward/record.url?scp=85042696635&partnerID=8YFLogxK
U2 - 10.1681/ASN.2017090997
DO - 10.1681/ASN.2017090997
M3 - Article
C2 - 29263159
AN - SCOPUS:85042696635
VL - 29
SP - 949
EP - 960
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
SN - 1046-6673
IS - 3
ER -