Did the Norris Lab Discover the Hypermobile EDS Gene?

With first author Cortney Gensemer PhD, the Norris Lab at Medical University of South Carolina released a preprint last week titled “Variants in the Kallikrein Gene Family and Hypermobile Ehlers-Danlos Syndrome.” The genetic marker(s) for hEDS (hypermobile Ehlers-Danlos Syndrome) IS unknown. Russell Norris, PhD and his team have been researching the genetics of this most common type of EDS. They discovered genetic variants, single nucleotide polymorphisms (SNPs), that are rare in the general population but occurred in 32.8% of the hEDS patients studied.

This is what you need to know.

What are genetic variants?

• DNA information is coded using 4 chemical bases: cytosine (C), adenine (A), guanine (G), and thymine (T).

• 99% of DNA has the same bases in all humans.

• A SNP is a change in a nucleotide, or single DNA location.

• SNPs (pronounced “snips”) are a type of genetic variation that are extremely common.

• Over 600 million SNPs have been found worldwide.

• Many SNPs do not affect a gene’s function.

• Genes are areas of DNA that code for proteins which carry out various functions in the body.

• SNPs such as those in kallikrein genes may increase the risk of disease via the production of defective proteins in the body.

• Find more information on DNA and SNPs here.

• Read more about genetics in this book chapter.

What are kallikrein genes?

• Kallikreins consist of 15 closely related, secreted serine proteases.

• Tissue kallikreins include 15 proteases encoded by genes found on chromosome 19q13.4.

• This constitutes the largest human genome protease gene cluster.

• Kallikrein-related proteases are numbered KLK1-KLK15.

• Learn more about kallikreins by visiting this page.

What gene for hypermobile EDS did the Norris Lab find?

• They found a genetic variant in two family pedigrees that is located in the kallikrein (KLK) serine-protease gene KLK15.

• This single nucleotide polymorphism (SNP) is rare in the population and is predicted to be damaging.

• 197 sporadic hEDS patients were studied and 76 total KLK variants were found, 48 of which were unique in the cohort.

• 32.8% of the 197 patients had at least one variant in a KLK gene.

How could a kallikrein SNP cause hEDS?

• Kallikreins are known to influence the connective tissue environment via interactions with the extracellular matrix.

• Kallikrein genes play a role in immune cell function and blood pressure regulation.   

• These impacts could potentially contribute to comorbidities like mast cell activation syndrome (MCAS) and postural orthostatic tachycardia syndrome (POTS).

• MCAS and POTS are comorbidities frequently observed in hEDS patients.

Do kallikrein genes affect other systems?

• There is a tight interaction between kallikreins and the innate immune system, specifically the complement system.

• Kallikreins can cleave complement 3 (C3) and 5 (C5) directly, which leads to the generation of C3a and C5a.

• Potent anaphylatoxins C3a and C5a increase mast cell activation inflammation.

• Dysregulation of the interconnected kallikrein system and the complement pathway can lead to pathological conditions such as hereditary angioedema (HAE).

• HAE involves excessive inflammation and tissue swelling, features frequently observed in patients with hEDS.

Does this explain hEDS variability?

• hEDS phenotypes (clinical picture) are highly variable despite the autosomal dominant mode of inheritance.

• KLK gene variants, such as KLK15G226D, may function primarily in a dominant-negative manner.

• Kallikreins auto-activate and catalyze activation of downstream kallikrein enzymes in a synergistic hierarchy.

• Damaging effects may result even from loss-of-function alleles producing subtle changes in expression levels.

How were mice involved?

• The Norris Lab team generated knock-in mice (mutant) to see what effects the gene variants found in humans would produce.

• Mice are frequently genetically engineered to help us better understand human disease.

What did they find in the genetically altered mice?

• The mutant mice had functional and structural connective tissue defects consistent with the hEDS clinical cohort.

• These effects were found within multiple organ systems.

• The mice had increased elasticity and reduced mechanical strength in their Achilles tendons.

• The mice had normal overall cardiac function.

• Valve dysfunction was observed in 83% of the mutant mice, with 80% having demonstrable mitral valve prolapse.

• Some mice had slightly enlarged aortic dimensions with a statistical trend toward significance.

What does this mean for YOU?

• If you have had whole exome sequencing (WES), your report may come back with one word, “NEGATIVE”, even if you have a variant in the KLK gene family or other variants of uncertain signifigance (VUS).

• Your ordering doctor may need to request your raw data to see if you have any variants in the KLK gene family or other VUS.

• hEDS remains a clinical diagnosis.

• Given the heterogeneity of hEDS, it is likely that multiple causative genes may be found.

• Your hEDS diagnosis should not be taken away if you do not have a KLK family variant.

Conclusion

Multiple factors likely contribute to the genotype-phenotype (genetic makeup-observable characteristics) correlation in hEDS. These include environmental exposures, incomplete penetrance, genetic background, potential under-diagnosis, and reduced expression.

These Norris Lab findings provide the first evidence for the involvement of kallikrein gene variants in hypermobile EDS.

Thank you to Cortney Gensemer, PhD, Russell Norris, PhD and the entire dedicated team at Medical University of South Carolina as well as all coauthors!   

These findings are vital to understanding more about hEDS and to the development of potential life changing treatments!

FAQs

Q:  Will my hEDS diagnosis be taken away if I don’t have a KLK15 variant?

A:  NO!

Q:  Is kallikrein (KLK) testing part of current connective tissue disorder panels?

A:  NO!

Q:  Can I get tested for variants in the kallikrein (KLK) gene group?

A:  Yes, if your doctor orders whole exome sequencing (WES) or other genetic testing that involves the kallikrein (KLK) family.

Q:  When will kallikrein (KLK) gene testing be part of connective tissue disorder panels?

A:   That is unknown.

Q:  I have variants of unknown significance (VUS) in other genes.  Does this mean that those are not significant?

A:  NO!

Q:  Will this change my treatment plan to manage hEDS symptoms?

A:  Hopefully these results will lead to effective new treatments for hEDS in the future.  Consult with your medical team to see if this information impacts how they approach your care.   

References

Cortney Gensemer, Tyler Beck, Lilong Guo et al. Variants in the Kallikrein Gene Family and Hypermobile Ehlers-Danlos Syndrome, 10 June 2024, PREPRINT (Version 1) available at Research Square

https://doi.org/10.21203/rs.3.rs-4547888/v1

More resources

View the most recent blog post coauthored with Dr. Gensemer, Dangerous EDS and HSD Myths Debunked by EDS Experts.

Read my blog post, Finding Better Healthcare with Ehlers-Danlos Syndrome: From a Physician with EDS.

Click here to read Dr. Gensemer's guest blog post, Hype, Hormones, and Hypermobility.

PS. The second sentence of this blog post (in purple) was edited from the original for improved clarity.