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Pathogenicity of a Human Laminin Β2 Mutation Revealed in Models Of BASIC RESEARCH www.jasn.org Pathogenicity of a Human Laminin b2 Mutation Revealed in Models of Alport Syndrome Steven D. Funk,1 Raymond H. Bayer,1 Andrew F. Malone,1 Karen K. McKee,2 Peter D. Yurchenco,2 and Jeffrey H. Miner1 1Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri and 2Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey ABSTRACT Pierson syndrome is a congenital nephrotic syndrome with eye and neurologic defects caused by mutations in laminin b2(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 polymeriza- tion, 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 path- ogenic. However, expression of LAMB2-S83R significantly increased the rate of progression to kidney failure 2 2 2 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 a3a4a5(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. J Am Soc Nephrol 29: 949–960, 2018. doi: https://doi.org/10.1681/ASN.2017090997 Basement membranes are thin sheets of extracellu- Significance Statement lar matrixconstructed from four major protein clas- ses: laminins (LMs), type IV collagens, nidogens, Pierson and Alport syndromes are genetic diseases that and sulfated proteoglycans.1,2 LMa,LMb,and affect the laminin and type IV collagen components, LMg chains assemble with a 1:1:1 stoichiometry respectively, of the glomerular basement membrane. Understanding the pathogenic mechanisms of muta- in the endoplasmic reticulum to form covalently tions found in patients may provide guidance for 3 linked heterotrimers. In the glomerulus, these choosing therapeutic approaches. Engineering a hu- man LAMB2 mutation that causes a delayed nephrotic syndrome and impairs laminin polymerization into the Received September 17, 2017. Accepted November 19, 2017. mouse resulted in no detectable defect in glomerular permselectivity. However, breeding just one copy of Published online ahead of print. Publication date available at this mutation onto the Alport mouse background dra- www.jasn.org. matically increased the rate of progression to ESRD, Correspondence: Dr. Jeffrey H. Miner, Division of Nephrology, suggesting a genetic interaction. Thus, variants in a Washington University School of Medicine, 4523 Clayton Ave- noncollagen GBM protein can affect progression of nue, Campus Box 8126, St. Louis, MO 63110. Email: minerj@ Alport syndrome. This could explain in part the variation wustl.edu in disease presentation and progression observed in patients with Alport syndrome. Copyright © 2018 by the American Society of Nephrology J Am Soc Nephrol 29: 949–960, 2018 ISSN : 1046-6673/2903-949 949 BASIC RESEARCH www.jasn.org are secreted into the space between podocytes and endothelial site mutations leading to absent or truncated LAMB2 protein. cells.4 The a-, b-, and g-chains’ laminin amino-terminal (LN) In contrast, LAMB2 missense mutations cause the less severe polymerization domains link LM heterotrimers together at nephrotic syndrome type 5 with or without ocular abnormal- a-b-g “trimeric nodes” to form a planar, sheet-like network ities (OMIM 614199).14,18 Most missense mutations cluster in in the matrix milieu, whereas the LMa chain’scarboxyl- or near the LN domain that mediates LM-521 polymeriza- terminal LM globular domain links the LM network to cell tion.14 Such LN domain mutations are logically predicted to surface receptors (e.g., integrins and dystroglycan).3,5 Simi- cause LM polymerization defects that should adversely affect larly, type IV collagens assemble intracellularly to form heter- GBM architecture and permselectivity, thereby causing ne- otrimeric “protomers” that are secreted into the extracellular phrotic syndrome. However, studies of two pathogenic mis- space, where distinct carboxyl-terminal and amino-terminal sense mutations in mice, LAMB2-R246Q and LAMB2-C321R, domain interactions promote collagen IV network formation.6 revealed a mechanism involving impaired protein folding and In the glomerular basement membrane (GBM), laminin a5b2g1 (LM-521) tri- mers form separate networks adjacent to podocytes and endothelial cells, and colla- gen a3a4a5(IV) (COL4A345) protomers form a network at the center of the GBM.7 A separate collagen a1a2a1(IV) network forms adjacent to the endothe- lium.7,8 Nidogen, a basement membrane protein with binding sites for LMg1and collagen IV, links the LM and collagen net- works.9 The long heparan sulfate proteo- glycan agrin links the LM-521 coiled coil domain to cell surface integrins and dys- troglycan.10 Collectively, these LM-cell, LM-nidogen, and nidogen-collagen IV interactions dictate the superstructure of the GBM, although the GBM con- tains numerous other extracellular matrix proteins.11 The GBM, the podocytes, and the endo- thelium interact to form the glomerular filtration barrier.12,13 The loss of podocyte slit diaphragm–associated proteins (neph- rin, podocin, CD2AP, etc.) or GBM com- ponents (laminin b2[LAMB2]or COL4A345)causesvariousformsofhe- reditary kidney disease that are always ac- companied by proteinuria. Loss of LAMB2, which prevents synthesis of LM- 521, causes Pierson syndrome, a congenital nephrotic syndrome with diffuse mesan- gial sclerosis and distinct ocular and neu- rologic abnormalities.14,15 Loss of any one of the collagen-a3, -a4, or -a5chains, which prevent or reduce production of the COL4A345 network, causes Alport Figure 1. LAMB2-S83R protein resulting from CRISPR/Cas9 mediated gene editing syndrome, a hereditary nephritis associ- accumulates in the GBM but is not pathogenic. (A) Sanger sequencing shows the heterozygous A to C mutation (asterisk) resulting in an Ser to Arg conversion; the ated with hearing and eye defects.16,17 boxed sequence is the WT, and the lower sequence is the mutant. (B) SDS-PAGE 2/S83R The pathophysiologic mechanisms under- analysis of urine shows the lack of elevated albuminuria in Lamb2 mice versus lying these diseases are incompletely theWTatupto13months(n=3–5). (C) Immunofluorescence analysis of LAMB2 in the +/+ +/S83R S83R/S83R understood. GBMs of Lamb2 (10 months), Lamb2 (10 months), Lamb2 (9 months), 2/S83R LAMB2 mutations that cause Pierson and Lamb2 (10 months) mice. LAMB2 levels in any S83R-containing mice were syndrome are typically nonsense or splice similar to the WT at any age up to 13 months; n=3–4 for each genotype. 950 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 949–960, 2018 www.jasn.org BASIC RESEARCH secretion and induction of endoplasmic reticulum stress.19,20 Such knowledge about the pathogenic mechanisms of individ- ual mutations can be informative for devising personalized therapies. In the interest of deciphering the pathogenic mechanisms of other LAMB2 mutations, we studied the LAMB2-S80R LN domain mutant, which was discovered as homozygous in a patient with delayed-onset, high-level albuminuria and is pre- sumed to be pathogenic.14,21 Proteinuria at 2 g/d was observed at age 5 years old and persisted for several years. By age 11 years old, the proteinuria worsened to 4.1 g/m2 per day. A biopsy at age 11 years old showed mild diffuse mesangial sclerosis and tubular atrophy. LMb2 immunostaining indicated that LAMB2-S80R is secreted and incorporates into the GBM sim- ilar to control. We engineered this mutation into mice in two different ways and found no evidence that it is pathogenic on its own. However, in the context of mouse models of Alport syndrome, the mutation behaved as a strong modifier allele that worsened disease progression. This provides the first ge- netic evidence that a variant in an LM gene can affect the pro- gression of kidney disease in Alport mice and suggests that even clinically silent variants in GBM-related genes may be capable of affecting the severity of the Alport phenotype in patients. RESULTS Expression of LAMB2-S83R in Transgenic Mice To validate the causality and investigate the mechanisms of pathogenicity of the human LAMB2-S80R mutation, we first generated transgenic mice expressing rat LAMB2-S83R (the analogous amino acid change in both rats and mice) in podo- cytes via the mouse nephrin promoter.22 Evaluation of trans- gene expression with an anti-rat LAMB2 antibody revealed relatively high, normal, or mosaic expression in three different lines (Supplemental Figure 1A), similar to our previous results from transgenic expression of LAMB2-C321R and LAMB2- R246Q mutant proteins.19,20 LAMB2-S83R colocalized with GBM nidogen, indicating secretion from podocytes and incorporation into the GBM (Supplemental Figure 1B) as ob- served in the biopsy of the patient with LAMB2-S80R.21 Trans- 2 2 genes that expressed were bred onto the Lamb2 / genetic background23–25 to test the function of the S83R mutant in the absence of wild-type (WT) LAMB2. Mice with relatively anti-LAMC1 signal was normalized to the number of nuclei and Figure 2. LAMB2-S83R impairs LM polymerization on Schwann calculated as the net summed intensity per cell of the signal de- cells in vitro.
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