Genetic Basis of Type IV Collagen Disorders of the Kidney - CJASN
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CJASN ePress. Published on April 13, 2021 as doi: 10.2215/CJN.19171220
Genetic Basis of Type IV Collagen Disorders of
the Kidney
Catherine Quinlan1,2,3 and Michelle N. Rheault 4
Abstract
The glomerular basement membrane is a vital component of the filtration barrier of the kidney and is primarily
composed of a highly structured matrix of type IV collagen. Specific isoforms of type IV collagen, the a3(IV), a4(IV),
and a5(IV) isoforms, assemble into trimers that are required for normal glomerular basement membrane function. 1
Department of
Disruption or alteration in these isoforms leads to breakdown of the glomerular basement membrane structure and Nephrology, Royal
function and can lead to progressive CKD known as Alport syndrome. However, there is wide variability in Children’s Hospital,
phenotype among patients with mutations affecting type IV collagen that depends on a complex interplay of sex, Melbourne, Victoria,
Australia
genotype, and X-chromosome inactivation. This article reviews the genetic basis of collagen disorders of the kidney 2
Department of
as well as potential treatments for these conditions, including direct alteration of the DNA, RNA therapies, and Kidney Regeneration,
manipulation of collagen proteins. Murdoch Children’s
CJASN 16: ccc–ccc, 2021. doi: https://doi.org/10.2215/CJN.19171220 Research Institute,
Melbourne, Victoria,
Australia
3
Department of
Introduction membranes have been described: a1-a1-a2(IV), Paediatrics, University
The glomerular basement membrane (GBM) is a vital a3-a4-a5(IV), and a5-a5-a6(IV) (2,3). The a1-a1-a2(IV) of Melbourne,
Melbourne, Victoria,
component of the filtration barrier of the kidney network is predominant in the developing GBM until Australia
and is primarily composed of a highly structured the capillary loop stage, when it is substantially 4
Division of Pediatric
matrix of type IV collagen, laminin, nidogens, agrin, replaced by an a3-a4-a5(IV) network (4). If any of Nephrology,
and perlecan (1). Disruption or alterations in these the a3(IV), a4(IV), or a5(IV) isoforms are absent due to Department of
components lead to breakdown of the GBM struc- Pediatrics, University
severe mutations (truncating mutations, for example),
of Minnesota Masonic
ture and function and can lead to progressive CKD. then the other type IV collagen isoforms are degraded, Children’s Hospital,
However, there is wide variability in phenotype and no a3a4a5(IV) heterotrimers are deposited in the Minneapolis,
among patients with mutations affecting type IV GBM, leading to Alport syndrome (2). In these pa- Minnesota
collagen that depends on a complex interplay of tients, the a1-a1-a2(IV) network persists, increasing
sex, genotype, and X-chromosome inactivation. This susceptibility to proteolytic degradation and leading to Correspondence:
article reviews the genetic basis of type IV collagen Dr. Michelle N.
progressive deterioration of the GBM and CKD (4).
Rheault, Division of
disorders of the kidney as well as currently available Milder mutations, generally missense mutations af- Pediatric Nephrology,
treatments and potential future genomic treatments fecting the glycine residues in the collagenous domain Department of
for these conditions. that are involved in triple-helix formation, may lead to Pediatrics, University
abnormally folded trimers that are either degraded or of Minnesota Masonic
Children’s Hospital,
lead to formation of an abnormal a3-a4-a5(IV) GBM 2450 Riverside
Type IV Collagen matrix. Patients with COL4A5 variants who express Avenue, MB680,
Six genes, COL4A1–COL4A6, encode six isoforms of the a3-a4-a5(IV) network in the GBM have a slower Minneapolis, MN
type IV collagen, a1(IV) to a6(IV). The genes are progression of kidney disease (median age of kidney 55454. Email:
rheau002@umn.edu
arranged in three pairs, COL4A1–COL4A2, COL4A3– failure .50 years) compared with those patients where
COL4A4, and COL4A5–COL4A6, situated in a head- the a3-a4-a5(IV) network is absent (median age of
to-head orientation on chromosomes 13, 2, and X, kidney failure 29 years) (5). Patients with Alport
respectively. The a(IV) isoforms share structural syndrome may also exhibit sensorineural hearing
features, including an amino-terminal sequence of loss due to the dysfunction of the a3-a4-a5(IV)
approximately 25 amino acids (7S), a collagenous network in the cochlea as well as ocular findings,
domain of approximately 1400 amino acids containing such as anterior lenticonus, due to presence of the a3-
multiple Gly-X-Y repeats where X and Y represent a4-a5(IV) network in the lens of the eye.
nonglycine amino acids, and a carboxy-terminal Variants in type IV collagen genes are distributed
(NC1) domain of approximately 230 amino acids. throughout each gene with no specific hot spots. Over
Type IV collagen isoforms self-assemble in the endo- 1500 unique variants have been reported in COL4A5,
plasmic reticulum to form triple helices in a very and over 500 each have been reported in COL4A3 and
specific stoichiometry. The presence of glycine at COL4A4 (6). For COL4A5, these are primarily mis-
every third residue in the collagenous domain is sense substitutions in 43% (33% in regions encoding
required for assembly of the triple helix. Three glycine within the collagenous domain and 10%
heterotrimers that occur in mammalian basement other); 34% nonsense mutations (both direct and
www.cjasn.org Vol 16 July, 2021 Copyright © 2021 by the American Society of Nephrology 12 CJASN
downstream); 23% splicing variants; 14% small deletions; and the benefit was greatest in those who started treatment
7% rearrangements or copy number variants; and small earlier (20). These findings were confirmed in a second
numbers of duplications, insertions, and indels (7). Both the cohort of Japanese patients with Alport syndrome where
phenotypic heterogeneity of Alport syndrome and the slow those treated with ACE inhibitors had a median age of
progression of the phenotype over decades make assigning kidney failure of .50 years, whereas those not treated had
pathogenicity using the American College of Medical a median age of kidney failure of 28 years (5). A prospective
Genetics and Genomics guidelines potentially problematic study of children with Alport syndrome showed a trend
(8). This has been addressed for variants in COL4A5 by the toward delay in progression of proteinuria in children who
development of variant databases, but phenotype genotype were treated with ramipril at very early stages of disease
correlation data lag behind for variants in COL4A3 and (urine albumin ,300 mg/g creatinine or isolated hematu-
COL4A4 (9,10). This will be addressed by the Clinical ria) (21). Given these findings, current treatment recom-
Genome Resource Variant Curation Expert Panels, an mendations suggest initiation of ACE inhibitors at the time
international collaboration aimed at resolving discrep- of diagnosis in men or boys with X-linked Alport syndrome
ancies in variant interpretation (9). and all patients with autosomal recessive Alport syndrome
and at initial development of albuminuria in women or
girls with X-linked Alport syndrome or all patients with
Alport Syndrome: Pathogenesis and Current autosomal dominant Alport syndrome (22).
Treatments Several other novel drugs are currently in clinical trials
If the a3-a4-a5(IV) trimer network does not form in the to treat Alport kidney disease, primarily targeting later
GBM during the capillary loop stage of glomerular devel- fibrosis signaling pathways. Lademirsen, an inhibitor of
opment, the a1-a1-a2(IV) network persists. Compared microRNA-21 (miRNA-21), is currently being tested in a
with the a3-a4-a5(IV) network, basement membranes phase 2 randomized controlled trial in patients with Alport
containing the a1-a1-a2(IV) network are less crosslinked syndrome at high risk of progression (NCT02855268).
and more susceptible to proteolysis by matrix metallo- Bardoxolone is an anti-inflammatory agent that acts via
proteases (2,11). The GBM with predominantly a1-a1-a2(IV) activation of Nrf-2 and inhibition of NF-kB to increase
network is also more distensible, leading to biomechan- eGFR. Studies in diabetic kidney disease demonstrate an
ical strain on the GBM affecting the adjacent endothelial increase in eGFR but were halted early due to a higher risk
cells and podocytes. Alport mice exposed to hypertension of hospitalization and death from heart failure (23).
with increased biomechanical strain on the GBM demon- Bardoxolone is currently being tested in phase 2/3 ran-
strate increased expression of matrix metalloproteinases domized controlled trials in patients with Alport syndrome
and inflammatory cytokines compared with wild-type mice with careful screening to minimize risk of cardiovascular
(12). In addition, biomechanical strain induces endothelin-1 disease (NCT03019185).
expression in endothelial cells in animal models of Alport
syndrome (13,14). Activation of endothelin type A receptors
on mesangial cells leads to mesangial filopodial invasion of Alport Syndrome: Clinical Correlation
the GBM with deposition of aberrant laminins, including Classic Alport syndrome is estimated to occur in 1:50,000
laminin 211, that can be blocked with endothelin receptor live births (24). Prevalence of milder forms of the disease
antagonists (13,15). Podocyte-derived invasions into the (heterozygous mutation in COL4A3 and COL4A4) is un-
GBM in Alport mice have also been described; however, known. X-linked Alport syndrome, caused by mutations in
the inciting trigger is unknown (16). Finally, aberrant COL4A5 on the X chromosome, accounts for 70%–80% of
signaling between the abnormal GBM and the podocyte via patients with Alport syndrome. Men with X-linked Alport
integrins also likely plays a role in Alport pathogenesis. syndrome invariably develop kidney failure, and their rate
Alport mice that have had integrin-a1 or integrin-a2 genes of kidney disease progression is strongly influenced by
additionally knocked out demonstrate reduced matrix genotype. In a European registry cohort, survival analysis
deposition, improved life span, and reduced expression demonstrated that large deletions and nonsense mutations
of matrix metalloproteases (17,18). Thus, the thickening conferred a 90% probability of kidney failure before age 30,
of the GBM in Alport syndrome over time appears to be compared with a 70% risk with splice site mutations and a
due to increased deposition of matrix from both podocyte 50% risk with missense mutations (25). Similar genotype-
and mesangial cell origin triggered by biomechanical strain phenotype correlations were reported in a Japanese cohort
and aberrant signaling between the GBM and adherent with median age of kidney failure of 18 years for patients
cells (Figure 1). with nonsense mutations and 40 years for patients with
Current standard of care for patients with Alport missense mutations (5). The position of a glycine sub-
syndrome includes inhibition of the renin-angiotensin- stitution may also affect the phenotype, as 59 glycine
aldosterone system to reduce the biomechanical strain on missense mutations are associated with a more severe
the abnormal GBM. Treatment of mouse models of Alport phenotype than 39 glycine mutations (26). The number of
syndrome with ACE inhibitors doubles the life span of side-chain carbon atoms in the substituting amino acid also
treated animals (19). Retrospective registry studies have influences the phenotype associated with a glycine
also shown an association between improved kidney substitution (27).
outcomes and ACE inhibition. A study from the European Women with heterozygous mutations in COL4A5 have a
Alport Registry included 283 patients with Alport syn- wide spectrum of disease from microscopic hematuria
drome and demonstrated that time to kidney failure was alone to kidney failure (28). In a large cohort of women
longer in patients who were treated with ACE inhibitors, with X-linked Alport syndrome, the risk of kidney failureCJASN 16: ccc–ccc, July, 2021 Collagen Disorders of the Kidney, Quinlan and Rheault 3
was 12% by age 45, 30% by age 60, and 40% by age 80 (29). Type IV collagen mutations may also contribute to
The explanation for the wide variability in outcomes for pathogenesis in other glomerular disorders. Thin basement
women with X-linked Alport syndrome is unclear but membranes have been observed on kidney biopsy in
is determined at least in part by X inactivation (30). The patients with familial IgA nephropathy (42). Pathogenic
a3-a4-a5(IV) heterotrimer is present in the GBM in a mosaic variants in COL4A3–5 were identified in nine of 46 families
pattern due to random X inactivation during fetal devel- with familial IgA nephropathy (43). In a genome-wide
opment. If by random chance more of the mutant COL4A5 association study of over 19,000 patients with diabetic
is expressed, kidney outcomes are worse. nephropathy, a common missense variant that encodes a
Homozygous or compound heterozygous mutations in tyrosine in place of aspartic acid at position 326 of the
COL4A3 and COL4A4 cause autosomal recessive Alport COL4A3 protein was identified that was protective against
syndrome, which accounts for approximately 5% of pa- the development of diabetic kidney disease (44). It was
tients with Alport syndrome. Kidney outcomes in autoso- hypothesized that the baseline thinning of the GBM
mal recessive Alport syndrome are similar to those in men associated with this variant prevented the GBM thickening
with X-linked Alport syndrome (31). Individuals with that occurs in diabetic kidney disease and was thus
heterozygous mutations in COL4A3 or COL4A4 also protective. However, in a smaller study of nine individuals
demonstrate a wide spectrum of disease from microscopic with diabetic kidney disease associated with maturity-
hematuria alone to progressive kidney disease and kidney onset diabetes in the young (MODY), variants in COL4A3
failure and are categorized as autosomal dominant Alport were associated with a more severe kidney phenotype (45).
syndrome (32). Previously, these patients may have been We are just beginning to understand the role of type IV
classified as having “thin basement membrane disease” on collagen mutations in patients with not only classic Alport
the basis of biopsy; however, a recent consensus report syndrome but other glomerular disorders as well.
recommended including all patients with heterozygous
mutations in COL4A3 or COL4A4 under the umbrella of
Alport syndrome given the similarities in GBM abnormal- Alport Syndrome Treatments: Future Genomic
ities and risk of progression requiring ongoing monitoring Strategies
(32). It has been increasingly recognized that autosomal Current treatments for Alport syndrome only slow the
dominant Alport syndrome accounts for a larger percent- progression of kidney disease, and most patients will still
age of patients with Alport syndrome than previously require kidney transplantation; thus, there is an unmet
recognized, up to 19%–31% of affected patients (33,34). need for novel, curative treatments. Understanding the
Digenic inheritance in Alport syndrome has also been cellular and molecular biology of the GBM opens up
described, including patients with dual COL4A3 and several avenues of genomic therapy for Alport syndrome,
COL4A4 variants and patients with COL4A5 and including gene editing, gene therapy, RNA therapy, and
COL4A4/3 variants in both cis and trans configurations chaperone therapy (Figure 2).
(35,36). Sequencing of the coding exons of all three type IV
collagen genes is important for diagnosis, even if the Gene Editing
inheritance pattern seems clear by pedigree analysis. Gene editing targets disease-causing genes to perma-
Heterozygous mutations in COL4A3 and COL4A4 also nently correct, remove, or replace a gene and, thus, cure the
may manifest as FSGS with or without classic GBM disease. Despite significant advances in ex vivo genome
findings of thinning or thickening with lamellation. This editing, it has been used in only a small number of human
association was first described in 2007 in a cohort of trials, largely due to concerns about off-target effects,
patients from Cyprus and has been reported numerous which could disrupt gene function.
times since then (37–39). Type IV collagen mutations are Stem cell transplantation is a less precise approach to
among the most common genetic mutations, identified in gene editing and has been tried in animal models of Alport
up to 31% of adults with familial FSGS (39) and up to 10% syndrome with promising results, including improvements
of a cohort of predominantly sporadic FSGS (40). It is in kidney function (46). Although mature podocytes are
unclear why some patients with heterozygous COL4A3 or thought to be incapable of replication, bone marrow may
COL4A4 mutations develop classic Alport syndrome kid- act as a podocyte progenitor niche, enabling some re-
ney phenotype, whereas others exhibit FSGS. generation of the GBM (47). Y chromosomes have been
demonstrated in the podocytes of male (XY) recipients of
female (XX) kidneys, suggesting that some limited regen-
eration is possible (48). Although patients with GBM
Type IV Collagen Mutations in Other Glomerular disease have had improvement in proteinuria following
Disease bone marrow transplants as part of leukemia treatment
Type IV collagen mutations are also frequently found in through recruitment of podocytes and partial expression of
patients with CKD who were previously unknown to have a3(IV) chains, this approach is not suitable for the majority
Alport syndrome. In a study from Columbia University, of patients (49). Care must be taken with interpretation of
3% of patients with CKD who underwent whole-exome stem cell–based experimental results in kidney disease
sequencing had pathogenic variants in COL4A3 (0.8%), because injection of amniotic fluid stem cells into COL4A5
COL4A4 (0.6%), or COL4A5 (1%), the majority of whom (2/2) mice before the onset of proteinuria has been shown
did not have a diagnosis of Alport syndrome (41). This to delay interstitial fibrosis and glomerular sclerosis, re-
finding highlights the problem of underdiagnosis of pa- duce the decline in kidney function, and prolong survival
tients with type IV collagen mutations. without podocyte differentiation, likely by reducing4 CJASN Figure 1. | Pathogenesis of Alport syndrome kidney disease progression. GBM, glomerular basement membrane. fibrosis (50). Bone marrow transplants carry a significant patient-specific stem cells underway (NCT03728322), it is mortality risk however; thus, they cannot be considered a likely that human trials for Alport syndrome will occur in the safe treatment for Alport syndrome at this time (51). next decade. Challenges to this approach include difficulties With experimental evidence showing it is possible to in manipulation of the podocyte in vivo. correct a clinically significant proportion of COL4A3 and Another approach to gene editing that may be explored COL4A5 variants in podocyte cell lines (52), and human trials in Alport syndrome is X-chromosome reactivation. for Hemophilia-B using infused CRISPR/Cas9-corrected X-chromosome inactivation occurs in early development Figure 2. | Potential genomic treatments for Alport syndrome. COL4A3, COL4A4, and COL4A5 are transcribed into RNA in the nucleus. The RNA is then translated into type IV collagen protein isoforms. These type IV collagen isomers self-assemble into trimers in the endoplasmic reticulum. After they are processed into trimers, they are secreted into the GBM. There are a number of potential targets for rectification of this process in the setting of pathogenic variants in type IV collagen.
CJASN 16: ccc–ccc, July, 2021 Collagen Disorders of the Kidney, Quinlan and Rheault 5
and ensures that female XX cells have similar expression to endoplasmic reticulum stress, unfolded protein response
male XY cells. In each cell, one X chromosome is randomly activation, and increased cellular apoptosis. Chaperone
epigenetically silenced and is referred to as the inactive X therapy uses small molecules to unfold abnormal proteins,
chromosome (Xi), in a process initiated by a molecule called enabling them to escape the endoplasmic reticulum and be
Xist (53). Because the phenotype of women with X-linked utilized by the cell.
Alport syndrome can vary from hematuria to kidney Examples of these agents in human use include Luma-
impairment depending on lyonization of the X chromosome, caftor (63), which binds directly to F508del-CFTR correct-
a potential treatment of severe X-linked Alport syndrome in ing its mislocalization, ameliorating the phenotype, and
women could be reactivation of the healthy copy of the transforming the outlook for people with cystic fibrosis,
COL4A5 gene on the Xi. A number of factors have been and Migalastat (64), which stabilizes mutant forms of a-Gal
identified that are involved in this pathway, and the use of and has shown promise as an alternative to enzyme
small molecule inhibitors targeted at these pathways has replacement for patients with Fabry disease.
been shown to reactivate Xi in mouse models of Rett Mouse models and human kidney biopsy samples of
syndrome (54). Human Genotype-Tissue Expression analysis COL4A3 disease have shown unfolded protein response
shows COL4A5 escapes Xi in the brain, although the effect of activation (65) as part of the pathogenesis of Alport
this is not understood (55). Biallelic expression of some syndrome. Treatment of cellular models of Alport syn-
X-linked genes in women has been shown to contribute to a drome with the chaperone sodium-4-phenylbutyrate has
portion of their reduced cancer incidence when compared shown reduced endoplasmic reticulum stress (66) and may
with men. Thus, Xi remains experimental at this point in time facilitate a5(IV) extracellular transport (67). Future clinical
due to significant concerns about off-target effects. trials targeting Alport phenotypes that lead to unfolded
protein response may result in improved outcomes when
started early in disease.
Gene Therapy
In gene therapy, the effect of a mutation is offset by
inserting a corrected copy of the gene into the body using a
vehicle while the disease-related genes remain in the RNA Therapy
There are currently three approaches to targeting RNA
genome. If the normal gene replaces the mutant allele,
for treatment of disease: single-stranded antisense oligo-
then transformed cells proliferate and produce enough
nucleotides (ASOs), short stretches of DNA that prevent
normal protein to restore a healthy phenotype. Effective
mRNA from being translated into a protein; RNA in-
delivery depends on a vehicle, such as a virus or nano-
terference, small interfering RNAs (siRNAs) degrade
particle, and an accessible tissue compartment. Thus far, it
mRNA and prevent it from being translated into protein
has been most successful for eye, blood, or bone mar-
and miRNAs, small noncoding RNAs whose functions
row disease (56).
include post-transcriptional regulation of gene expression;
The feasibility of gene therapy has been shown in mouse
and RNA vaccines, introducing mRNA into the body
models of Alport syndrome with an inducible transgene
reprograming the cell to produce a specific protein.
system, where secretion of a3a4a5(IV) heterotrimers by
Exon skipping therapy using an ASO has been investi-
podocytes into a preformed Alport GBM was effective at
gated as a therapy for a small group of patients with a
restoring the missing collagen IV network, reducing pro-
specific variant in COL4A5. Genotype-phenotype correla-
teinuria, slowing disease progression, and increasing sur-
tion data show that some individuals with COL4A5
vival (57). Adenovirus-mediated gene transfer into kidney
variants experience a milder clinical course, raising the
glomeruli has also been demonstrated in mouse models of
question of whether exon skipping could nudge the genetic
Alport syndrome (58). However, inducing expression of
code toward a milder phenotype. For example, pub-
COL4A3 in mice using an endothelial cell–specific inducible
lished data have shown that specific COL4A5 gene splice
transgenic system does not result in restoration of the
site mutations with in-frame deletions showed a good
a3a4a5(IV) heterotrimer or resolution of the Alport phe-
kidney prognosis when compared with an out-of-frame
notype (59). Successful delivery of COL4A5 into swine
deletion group (68). On the basis of these data, Yamamura
kidney by an adenovirus vector has been reported with
et al. (69) have developed an exon-skipping therapy using
deposition of a5(IV) into the GBM (60). Unfortunately, this
an ASO targeting truncating variants in exon 21 of the
technique required direct infusion of vector into the renal
COL4A5 gene.
artery, which is not feasible for translation to widespread
In patients with truncating variants in COL4A5, the
human application.
a5(IV) chain will terminate at the stop codon, and the NC1
Although CRISPR/Cas9 gene editing in the kidney has
domain is missing. In contrast, exon-skipping therapy will
not yet moved beyond proof of concept, it may be that
replace the truncating variant with an in-frame deletion
ocular gene therapy will be utilized at an earlier time point
variant at the transcript level, and the NC1 domain is not
than kidney targeting with delivery of the viral vector
lost, leading to the formation of the trimer and restoration
directly into the eye (61), where clinical trials and licensed
of the GBM. Mice treated with this protocol had
gene replacement therapy are further advanced (62).
a3a4a5(IV) triple-helix formation with clinical and path-
ologic improvements, including expression of the a5(IV)
Chaperone Therapy chain on GBM and tubular basement membrane with
Missense mutations can result in the production of prolonged survival time. Exon skipping does not aim to
misfolded proteins, which are retained in the endoplasmic “cure” the disease but induces a frameshift that leads to the
reticulum, the quality control center of the cell. This leads to expression of a milder phenotype. The future potential for6 CJASN
this approach includes establishing mutant mouse models of Melbourne and serving as section editor for Nephrology.
for other exons that could be targeted by an ASO and will M.N. Rheault reports employment with the University of
rely on large genomic datasets of individuals with path- Minnesota; receiving research funding from Advicenne, Reata,
ogenic variants in COL4A5. There may be significant risk Travere, and Sanofi; and serving on the Alport Syndrome Foun-
with this approach given that benign hypomorphic vari- dation Medical Advisory Board, NephJC (501c3) Board of Directors,
ants in gnomAD, such as COL4A5 c.1871G.A, and Pediatric Nephrology Research Consortium (501c3) Steer-
p.(Gly624Asp), have also been implicated in the develop- ing Committee.
ment of a severe disease (70).
RNA interference can use miRNA, a small, noncoding
RNA molecule whose functions include post-transcriptional Funding
regulation of gene expression. There are a number of None.
miRNAs that are thought to play a role in the progression
of CKD, with several shown to be upregulated in fibrotic References
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