KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome, 2025, Gensemer et al

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Eddie

Senior Member (Voting Rights)
This is the preprint published in 2024.
The paper was published in 2025 with the new title. See post #10.

Variants in the Kallikrein Gene Family and Hypermobile Ehlers-Danlos Syndrome, 2024, Gensemer et al
Abstract

Hypermobile Ehlers-Danlos syndrome (hEDS) is a common heritable connective tissue disorder that lacks a known genetic etiology. To identify genetic contributions to hEDS, whole exome sequencing was performed on families and a cohort of sporadic hEDS patients.

A missense variant in Kallikrein-15 (KLK15 p. Gly226Asp), segregated with disease in two families and genetic burden analyses of 197 sporadic hEDS patients revealed enrichment of variants within the Kallikrein gene family.

To validate pathogenicity, the variant identified in familial studies was used to generate knock-in mice. Consistent with our clinical cohort, Klk15G224D/+ mice displayed structural and functional connective tissue defects within multiple organ systems.

These findings support Kallikrein gene variants in the pathogenesis of hEDS and represent an important step towards earlier diagnosis and better clinical outcomes.

https://www.researchsquare.com/article/rs-4547888/v1?redirect=/article/rs-4547888
 
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Significant enrichment for qualifying variants was observed in 11 of the 15 KLK genes with p-value <0.05 as well for the entire KLK gene cluster (considered as whole, p = 2.28×10−14)
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Exploring the molecular consequences of Kallikrein variants will not only uncover mechanisms of normal connective tissue development and disease but also shed light on the comorbidities commonly associated with hEDS. Notably, Kallikreins are known to interact with substrates in the extracellular matrix, influencing the connective tissue environment in both homeostasis and disease. This class of genes also plays roles in blood pressure regulation and immune cell function, potentially contributing to various comorbidities such as postural orthostatic tachycardia syndrome (POTS) and mast cell activation syndrome, which are frequently observed in hEDS patients
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Relatedly, it is curious that there is a tight interaction between Kallikreins and in the innate immune system, specifically the complement system. Kallikreins can cleave complement 3 (C3) and 5 (C5) directly, leading to the generation of C3a and C5a, which are potent anaphylatoxins that enhance inflammation upstream of mast cell activation.
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we evaluated the genetic burden of the entire KLK family of genes in a larger hEDS cohort. [Whole Exome Sequencing] was performed on 197 clinically diagnosed, unrelated hEDS patients and filtered for KLK variants with [Minor Allele Frequencies] less than 0.01 (<1%) in gnomAD. A total of 76 variants were identified, with 48 being unique in the cohort and 65 patients having at least one rare variant in a KLK gene (32.8%). A gene-based burden test was used to evaluate enrichment of rare variants in individual KLK genes and the entire contiguous gene cluster in hEDS patients. Significant enrichment for qualifying variants was observed in 11 of the 15 KLK genes with p-value <0.05 as well for the entire KLK gene cluster (considered as whole, p = 2.28×10−14 ) thus supporting a broad role for Kallikrein genes in hEDS.
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Screenshot 2024-06-13 at 9.20.40 AM copy.jpg

Also:

Previous reports have made claims for the involvement of the Methylenetetrahydrofolate reductase (MTHFR) gene. We performed genetic-follow up analyses in our WES cohort of 197 individuals and did not observe a significant enrichment of the common MTHFR polymorphisms.
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As far as I can see this is just a report of a gene variant in two families with EDS. I would forget the hEDS. In these families it is presumably the basis of their EDS, which I guess has limited visceral involvement and so comes under type III (hyper mobile type) although the knock in mice had other organs involved.

I don't think it is of any relevance to ME/CFS. It is just another very rare gene found in two EDS families. EDS isn't really a disease. It is a rag-bag of about a hundred different rare dominant gene defects affecting connective tissues.
 
I am not hypermobile so I don't have real personal interest in this area, other than curiosity.

I would agree that if it were just the two EDS families it would have no relevance to hEDS. However, given they looked at a larger cohort it seems like there is some signal there, even if these mutations did not occur in everyone.

@Jonathan Edwards if the finding that 33% of hEDS patients have a rare variant in the KLK gene was found to be generally applicable, do you think that would justify the use of the hEDS label in people who had that variant? Is it plausible that there are other variants that create generalized hypermobility issues without being caused by a single currently identified gene? Just like the EDS label refers to a set of rare gene defects affecting connective tissues, perhaps hEDS refers to a slightly different presentation due to different or multiple gene defects.

Of course, even if that is the case, the connection to ME/CFS would still be tenuous.
 
Eddie said:
Just like the EDS label refers to a set of rare gene defects affecting connective tissues, perhaps hEDS refers to a slightly different presentation due to different or multiple gene defects.
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The basic point is that EDS is defined as a monogenic dominant or sex linked recessive disorder. There has always been a group called type III, or hypermobile only. The problem with the term hEDS is that it has become a standard term simply for hypermobility, which in 99% of cases will be polygenic and not EDS at all.

The only sensible thing to do at this stage is to reclassify EDS according to individual gene defect. The original set of types (maybe 13) were never based on anything other than vague similarity. There aren't 13 defects, there are many more. Each one will have a different spectrum of problems. Much better to identify each person as having EDS with gene mutation xyzzy and to stop using EDS or hEDS for a wider spectrum of hypermobility.
 
Jonathan Edwards said:
The basic point is that EDS is defined as a monogenic dominant or sex linked recessive disorder. There has always been a group called type III, or hypermobile only. The problem with the term hEDS is that it has become a standard term simply for hypermobility, which in 99% of cases will be polygenic and not EDS at all.

The only sensible thing to do at this stage is to reclassify EDS according to individual gene defect. The original set of types (maybe 13) were never based on anything other than vague similarity. There aren't 13 defects, there are many more. Each one will have a different spectrum of problems. Much better to identify each person as having EDS with gene mutation xyzzy and to stop using EDS or hEDS for a wider spectrum of hypermobility.
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That makes a lot of sense to me, thanks
 
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