Collagens are a family of proteins that are collectively the most abundant protein in
the body, and can be found throughout the various connective tissues.
Each member of the family is named with a Roman numeral, and if mutated or absent, can
lead to problems in the tissues where that particular collagen is found.
Alport syndrome occurs as a result of mutations in Type IV collagen, which is particularly
important in the glomerulus of the kidney, the eye, and the cochlea, and that's why
the symptoms of Alport syndrome are specific to those tissues.
Type IV collagen is a sheet-like structure found in all basement membranes and serves
to support cells and form barrier.
The three basement membrane layers are the lamina lucida, lamina densa (where type IV
collagen is), and lamina reticularis.
Now within the kidneys, there are glomeruli, which filter the blood and that together with
a tubule forms a nephron.
These glomeruli happen to have a basement membranes, called the glomerular basement
membrane, or GBM, and that GBM, along with the fenestrated, meaning has pores, capillary
endothelium and the podocyte slit diaphragm, forms a selective filter, meaning that water
and certain other plasma components can escape the capillary, forming the filtrate that will
become urine, but red blood cells and most proteins stay in the glomerular capillary.
In Alport syndrome, kidney function is normal through early childhood, but over time, the
missing or nonfunctional type IV collagen causes the GBM to become thin and overly porous.
This allows red blood cells to pass right through from the capillary to the urinary
filtrate leading to microscopic hematuria, which is where red blood cells are seen in
the urine under a microscope, and this might eventually lead to gross hematuria, where
the red blood cells can be seen with the naked eye.
Over time, excessive amounts of protein start to get through the filter, resulting in proteinuria,
or in protein in the urine.
And finally this excessive protein loss and other factors cause the GBM to undergo sclerosis.
As there are less and less healthy glomeruli, somebody with Alport syndrome might develop
renal insufficiency or even failure, which can lead to renovascular hypertension as well.
Together the hematuria, renal insufficiency, and hypertension contribute to the categorization
of Alport syndrome as a glomerulonephritis.
Another cause of glomerulonephritis called Goodpasture syndrome is caused by autoantibodies
against the basement membrane in the glomeruli and the alveoli.
So although abnormality in the basement membrane is from a different cause, the result is similar
in these two syndromes.
Another part of the body affected in Alport syndrome is the ear, which can lead to hearing
loss, and usually this isn't present at birth, but starts in childhood or adolescence,
and the precise mechanism is unclear.
One proposed mechanism involves the cochlea or inner ear structure which contains the
Organ of Corti, which has really small, but highly specialized set of hair cells that
are attached to a basement membrane.
Abnormal type IV collagen might prevent those hair cells from generating normal nerve signals
in response to sound vibrations.
Because it's an inner ear problem, this is a type of sensorineural hearing loss, as
opposed to middle ear and outer ear problems, which would lead to conductive hearing loss.
Some patients with Alport syndrome also have eye findings, which are also not typically
present at birth.
These include anterior lenticonus, where the center part of the lens starts to push into
the anterior chamber because the anterior lens capsule lacks the integrity to maintain
the shape of the lens.
Myopia, or nearsightedness, and lens opacities can result as well.
Other eye changes in Alport syndrome include having white or yellow flecks around the macula,
which is the central part of the retina, as well as having problems with the cornea, like
recurrent erosions.
Type IV collagen is a heterotrimer, meaning that it's made up of three different polypeptide
subunits, which are each composed of an alpha chain, and that fit together in a triple helix.
Each alpha chain has a very long repetitive amino acid sequence, with glycine followed
by two variable amino acids, repeated over and over.
Just remember that this is a repeat of amino acids, not a DNA triplet repeat.
Now glycine is the smallest amino acid, which allows it to fit tightly into the triple helix
of collagen, if a mutation causes a larger amino acid to get put in place of glycine,
then that regular helix can't be packed as tightly and might get degraded.
Now there are six similar alpha chains to choose from when building a collagen IV trimer,
which are encoded by six genes with names that start with COL4, for collagen IV, and
then an A since they code for alpha chains, and a number 1-6 to designate which alpha
chain.
One version of type IV collagen combines the alpha-3, alpha-4, and alpha-5 chains; another
combines two alpha-1's with an alpha-2; a third version has two alpha-5's and an
alpha-6.
The alpha-1/alpha-1/alpha-2 collagen IV is present in basement membranes at birth, but
during infancy it gets replaced by the alpha-3/alpha-4/alpha-5 collagen IV, particularly in the glomerulus,
inner ear , and the eyes.
When there's a mutation in the COL4A3, COL4A4, or COL4A5 genes, the alpha-3/alpha-4/alpha-5
heterotrimer is affected and this causes Alport syndrome.
COL4A5 is on the X-chromosome, so mutations in it can cause X-linked Alport syndrome,
which presents early on and is the most common form of Alport syndrome.
COL4A3 and A4 are on autosomes, meaning non-sex chromosomes, and mutations in these cause
either autosomal recessive Alport syndrome, which is also early onset, or autosomal dominant
Alport syndrome, which causes late onset disease.
Also, mild mutations in COL4A3 and A4 can cause thin basement membrane nephropathy,
where microscopic hematuria is the only symptom.
For diagnosis, Alport syndrome is typically suspected when there are clinical signs like
gross hematuria or if there are vision or hearing problems, or microscopic hematuria
with no apparent cause.
A family history of Alport syndrome is also a good clue, but it also might be absent in
cases of recessive Alport syndrome or new spontaneous mutations.
To confirm the diagnosis, a kidney or skin biopsy is often analyzed by immunohistochemistry,
meaning a labelled antibody is applied to a biopsy sample on a slide.
Since misfolded collagen tends to get degraded, absent staining for collagen alpha chains
suggests Alport syndrome.
Skin is easier to biopsy, and although it contains the alpha-5/alpha-5/alpha-6 form
of type IV collagen, it doesn't have any alpha-3 or alpha-4 chains, so it can only
be used to detect alpha-5 chain mutations.
Alternatively, the biopsy can be looked at under an electron microscope, which early
in disease would show GBM thinning, while later in disease would show a GBM with both
thin and thick, abnormal segments and a lamina densa that appears split, with strands that
look like a woven basket.
Finally some people might have gene testing for the COL4A genes.
The treatment for Alport syndrome usually focuses on the symptoms.
Proteinuria is treated with angiotensin converting enzyme inhibitors and/or angiotensin receptor
blockers because there is evidence that this prevents progression to kidney failure.
Anterior lenticonus can be treated with a replacement lens, and Kidney failure necessitates
dialysis or even kidney transplant.
Okay, as a quick recap, Alport syndrome is due to a mutation in genes COL4A 3, 4, and
5, which encode for type IV collagen alpha subunits 3, 4, and 5, and this causes kidney
problems like hematuria and eventually glomerulonephritis, inner ear problems like sensorineural hearing
loss, and eye problems like anterior lenticonus.
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