Ehlers-Danlos syndrome: Year of the Zebra
Ehlers-Danlos syndrome is a group of related genetic conditions which are all caused by defective collagen synthesis. Normally, collagen provides strength and elasticity to our bodies, and it’s found in the skin, ligaments, tendons, and bones.
In Ehlers-Danlos syndrome, defective collagen leads to stretchy skin, easy bruising, and joints that are super flexible.
Now, the cells that produce collagen are fibroblasts, and they make five types of collagen. These five types have specific parts of the body they call home.
Type I collagen makes its home in the skin, tendons, organs, and bones. Type II collagen makes its home in the cartilage.
Type III collagen, in reticular fibers, form a supporting mesh for soft organs like the liver and blood vessels. Type IV collagen is found in a foundation called the basal lamina, on which the epithelial cells sit.
The name of the genes that encode for a collagen type usually starts with the prefix COL, followed by the collagen number type, and the pro-alpha-chain it encodes.
There are many genes that encode for the different types of collagen, like COL1A1, COL1A2, COL3A1, COL5A1, and COL5A2. Let’s take the genes COL5A1 and COL5A2 that encode for type V collagen as an example.
In COL5A1, COL stands for collagen. The five stands for type V collagen and the A1 refers to an alpha-1-chain.
So, COL5A1 encodes a collagen type V alpha-1-chain. Now, to synthesize type V collagen, for example.
COL5A1 and COL5A2 get transcribed from DNA to mRNA and then gets translated from mRNA to into a string of amino acids that make up a protein.
This process happens many times over. Now, this string of amino acids consists mostly of glycine and two other random amino acids, usually, proline and lysine that repeat over and over as amino acid triplets.
Ultimately, this peptide forms what is called preprocollagen which can be a collagen type V alpha-1-chain or a collagen type V alpha-2-chain depending on the gene that encodes the protein.
Next, preprocollagen undergoes hydroxylation which is where two enzymes called prolyl hydroxylase and lysyl hydroxylase, with the help of many cofactors like vitamin C, add hydroxyl groups OH− onto proline and lysine.
Then there’s a process called glycosylation, which is done by two enzymes, galactosyl, and glucosyltransferase which add glucose or galactose monomers onto the hydroxyl groups.
After that, three of these chains twist into a triple helix called procollagen. Now, two combinations can make up the helix or procollagen for type V collagen, three type V alpha-1-chains or two type V alpha-1-chains and one type V alpha-2-chain.
The procollagen is then put in a vesicle by the Golgi apparatus and sent off into the extracellular space. In the extracellular space, procollagen undergoes proteolytic processing.
That’s where a tiny band of enzymes called collagen peptidases cleave the loose strands at both ends of the procollagen protein, turning procollagen into tropocollagen.
At this stage, tropocollagen is the mature type V collagen. Finally, there’s a stage called cross-linking, which is where lots of tropocollagen molecules, in this case, type V collagen, bind together with the help of a copper-dependent enzyme called lysyl oxidase to form a stack of collagen fibrils with Type I collagen.
Now, the cause of Ehlers-Danlos syndrome is typically due to a mutation on a gene that encodes for a type of collagen protein.
The name of the gene that encodes for collagen usually starts with the prefix COL. The specific gene involved determines the type of Ehlers-Danlos syndrome.
So for example classical Ehlers-Danlos or cEDS for short is caused by mutations in the COL5A1 and COL5A2 collagen V genes.
These genes are passed through autosomal dominant inheritance where only one mutant allele is needed for the disease. Vascular Ehlers-Danlos or vEDS is caused by a mutation in the COL3A1 gene which causes a decrease in Type III collagen synthesis which weakens blood vessels.
There are also cases where there’s a mutation in a gene called TNXB which causes a defect in a protein called tenascin-X.
Tenascin-X is believed to play a role in regulating the production and assembly of certain types of collagen and providing more flexibility.
A TNXB mutation is thought to be the cause of classical-like Ehlers-Danlos or clEDS in some people. Sometimes Ehlers-Danlos syndrome is not caused by a mutation on a gene that encodes for collagen but rather a gene that encodes for an enzyme that assists in the synthesis of collagen.
An example is kyphoscoliotic Ehlers-Danlos or kEDS where there’s insufficient lysyl hydroxylase which is an enzyme needed for the hydroxylation step.
There’s also musculocontractural Ehlers-Danlos or mcEDS, which is where there’s a defect in the collagen peptidases which leads to a block in the proteolytic processing step.
In classical-like, kyphoscoliotic and musculocontractural Ehlers-Danlos syndrome, the mutation is passed through autosomal recessive inheritance, which is where two mutant alleles are needed for the disease.
Finally, for hypermobile Ehlers-Danlos or hEDS, which makes up over 90% of people with EDS, no genetic mutation has been identified.The symptoms of Ehlers-Danlos syndrome include areas that rely heavily on collagen like the joints and skin.
Specifically it can lead to overly flexible joints, easy bruising, fragile and elastic skin.The diagnosis is mainly based on spotting the characteristic symptoms and examining the joints and the skin .
For the types associated with specific genetic mutations, diagnosis can be confirmed with DNA studies that can help identify the mutation.
In terms of treatment, individuals with Ehlers–Danlos syndrome are given supportive care, like physiotherapy to supporting bones and joints as well as orthopedic instruments like bracing, a wheelchair, and casting.
Alright, as a quick recap, Ehlers-Danlos syndrome is a group of similar genetic conditions caused by faulty collagen synthesis.
There are various subtypes, some of which follow autosomal dominant inheritance, whereas other follow autosomal recessive inheritance.
In which the hallmarks of symptoms are stretchy skin, easy bruising, and joints that are super flexible. collagen like the joints and skin Specifically it can lead to overly flexible joints easy bruising and fragile and elastic skin The is the diagnosis is mainly based on spotting the characteristic symptoms and examining the joints and the skin for the types associated with specific genetic mutations Diagnosis can be confirmed with DNA studies that can help identify the mutation in terms of treatment Individuals with Ehlers Danlos syndrome are given supportive care like physiotherapy to support bones and joints as well as orthopedic instruments like bracing a wheelchair and casting All right as a quick recap Ehler Staloff syndrome is a group of similar genetic conditions caused by faulty collagen synthesis There are various subtypes some of which follow autosomal dominant inheritance whereas others follow autosomal recessive inheritance The is the hallmarks of the of the symptoms are stretchy skin easy bruising and joints that are super
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