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Gene & Protein in Disease Alport syndrome: Genetics, variability, and management

1. Introduction genetic and environmental modifiers may play a crucial
role in mitigating the clinical expression of AS, leading to
Alport syndrome (AS) is a genetic disorder typically known considerable variability in disease manifestation. 6
by its’ triad: Progressive kidney disease, sensorineural
hearing loss, and ophthalmological abnormalities. It is 3. Genetic background and phenotypic
currently the second most frequent inherited nephropathy correlation
and an important etiology of end-stage kidney disease
(ESKD) worldwide. It results from variants in genes Collagen is an essential structural protein in the
1
encoding type IV collagen: COL4A5 on the X chromosome extracellular matrix, with 28 distinct types in vertebrates.
and COL4A3 and COL4A4 on chromosome 2. Disease- These are classified into fibrillar collagens (e.g., collagen I),
related variants in these genes lead to compromised network-forming collagens (e.g., collagen IV), beaded
synthesis, assembly, and/or function of α3, α4, and α5 microfibril collagens (e.g., collagen VI), multiplexins
chains of type IV collagen (COL4). This disruption leads to (e.g., collagen XV and XVIII), and fibril-associated
an abnormal trimerization of COL4 into a stable network, collagens with interrupted triple helices (FACITs) such
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impairing the integrity and function of glomerular, as collagen VII and XVII. Each type plays a specific role
cochlear, and ocular basement membranes. 1-3 in various tissues, contributing to their mechanical and
biochemical properties.
AS can be transmitted in several ways: X-linked
(XLAS), autosomal recessive (ARAS), autosomal dominant The collagen IV family consists of six distinct alpha
(ADAS), and, more recently, digenic inheritance has been chains (α1 to α6), each encoded by COL4A1 through
recognized. XLAS arises from pathogenic variants in the COL4A6 genes, respectively. These chains assemble into
COL4A5 gene, ARAS, and ADAS by pathogenic variants three heterotrimers (α1α1α2, α3α4α5, and α5α5α6) that
in COL4A3 or COL4A4, following a recessive or autosomal will ultimately create a critical network for the integrity and
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dominant inheritance pattern, respectively. The more function of basement membranes. The α1α1α2 is broadly
recently recognized digenic inheritance pattern occurs distributed throughout the body, whereas α3α4α5 and
when two different pathogenic variants are present in α5α6α5 networks have a more tissue-specific expression.
combination. 4 The α3α4α5 network is mainly found in the glomerular
basement membrane (GBM) of the kidney, cochlea in the
2. Prevalence inner ear, and the lens capsule of the eye, thus leading to
AS when mutated. Because the α1α1α2 network is a form
The true prevalence of AS is unknown, with estimates of ubiquitous, broadly distributed network, mutations in
varying widely depending on geographic and COL4A1 and COL4A2 tend to result in more heterogenous
methodological differences. Traditionally, the combined phenotypes than in AS. This explains why COL4A1
phenotype-based prevalence of XLAS and ARAS has been mutations are linked to conditions such as HANAC
reported between 1 in 5,000 and 1 in 50,000 in the United syndrome, where kidney involvement is generally mild,
States and Europe, respectively. 1 often presenting with multiple cysts or isolated hematuria,
However, population-based genome sequencing rather than the progressive nephropathy characteristic
9,10
analysis suggests a much higher prevalence of pathogenic of AS. COLA42 mutations seem also to be involved
COL4A5 variants, with approximately 1 in 2,320 in cerebral small vessel disease, being associated with
individuals carrying a potentially disease-causing variant. intracerebral hemorrhage. 11
Similarly, heterozygous variants in COL4A3 and COL4A4 Clinically, the hallmark triad of AS – progressive
are even more common, affecting approximately 1 in 106 nephritis, hearing loss, and ocular anomalies – derives
individuals. These variants, while often asymptomatic, primarily from observations of affected males with XLAS.
5,6
can manifest as hematuria or proteinuria and account for a However, the clinical manifestations vary significantly
significant proportion of previously unrecognized chronic based on inheritance pattern and the degree to which
kidney disease (CKD) cases. Homozygous or compound specific pathogenic variants disrupt the structure of the
heterozygous variants in COL4A3 or COL4A4 are rarer, α-chains. 1,2
with an estimated prevalence of around 1 in 88,866. 5
Kidney involvement is the hallmark of AS, with persistent
Moreover, the actual prevalence is likely higher when microscopic hematuria often serving as the earliest and
considering individuals already diagnosed with the disease most consistent finding. This feature typically presents in
1
and additional genetic variants not included in these early childhood and is frequently asymptomatic, identified
analyses. The unexpectedly high frequency of predicted only through family screening or routine urinalysis. Gross
pathogenic COL4A3 – COL4A5 variants implies that hematuria, though less common, may occur episodically,

Volume 4 Issue 2 (2025) 2 doi: 10.36922/gpd.7656