hEDS and the Kallikrein Gene Family

A lay summary of findings from the Norris Lab Preprint

Hypermobile Ehlers-Danlos Syndrome 

The Ehlers-Danlos Syndromes (EDS) are a group of 14 genetic disorders affecting connective tissues, which support cells, tissues and organs in the body. Common features of EDS include joint hypermobility (where joints can move beyond the normal range), fragile tissues, and the involvement of multiple organs and comorbidities.

Hypermobile EDS (hEDS) is the most common form of EDS but has historically lacked a clear genetic cause. People with hEDS may experience frequent joint dislocations, loose tendons and ligaments, stretchy skin, fragile connective tissue, and chronic pain. Additionally, hEDS can affect the gastrointestinal tract, cardiovascular system, and immune system. Diagnosing hEDS can be challenging due to the varied symptoms, lack of clinical awareness, and the absence of genetic markers, often leading to delays of several decades and worsening health outcomes.

While most types of EDS are incredibly rare diseases, hEDS is not rare. Due to the complex nature of the disease, it is expected that there will be many genetic factors involved (and likely environmental factors contributing as well).

Study Objective

To identify genetic causes for hEDS, researchers in the lab of Dr. Chip Norris at the Medical University of South Carolina (MUSC) developed a genetic registry to study families and unrelated individuals affected by hEDS. A new preprint summarizes one of the discoveries made by our group so far. Please note that this preprint has not yet been peer-reviewed and its final version is subject to change. 

Genetic Discovery in Two Families with hEDS

The study started with a family with autosomal dominant hEDS, which means the disorder is passed from one generation to the next. The study involved 11 family members, with 5 meeting the clinical diagnostic criteria for hEDS and 3 considered probable cases due to their age and clinical history consistent with an hEDS diagnosis. Whole exome sequencing (WES), a type of genetic analysis, was performed on two distantly related family members and found rare genetic variants (mutations) shared by the affected individuals. Among these, only one variant in the KLK15 gene matched perfectly with the hEDS symptoms in the family, meaning all people who were affected had that variant, and those who were unaffected did not. This same variant was also found in another smaller family with hEDS. 

This variant is located in the KLK15 gene and changes one amino acid in the protein it produces (Gly226Asp). This variant is uncommon in the general population and is predicted to be damaging to the gene's function. 

Kallikrein-related peptidase 15

KLK15 is a gene that produces an enzyme called kallikrein-related peptidase 15. This enzyme is part of the kallikrein family, a group of enzymes which help break down other proteins, and are found in many tissues (including connective tissue). These enzymes are important for various body functions, including helping to rebuild and maintain tissues.

Genetics in a Larger Cohort

The study was then expanded to the whole KLK gene family to see if it has a role in hEDS. WES was performed on a larger group of 197 hEDS patients. This revealed 76 uncommon gene variants in KLK genes, with 65 patients having at least one of these variants. The study found a higher frequency (statistical enrichment) of these variants in 11 out of the 15 KLK genes in hEDS patients compared to the general population, suggesting these genes play a significant role in hEDS.

A mouse model of KLK15 G226D

Next, researchers used a gene-editing tool called CRISPR-Cas9 to create mice with the KLK15 variant. This means they changed the mice's genes to have the same variant found in some people. Because all the mice are otherwise genetically identical, scientists can study the exact effects of this single genetic change. They looked at the Achilles tendons of these mice and found that the collagen fibers were smaller and more elastic. This matches the symptoms seen in the families studied, supporting the idea that the KLK15 gene plays a role in hEDS. By using animal models, researchers can validate genetic findings, understand the disease better and develop treatments.

In addition to Achilles Tendons, analysis was performed on the hearts of mice with the KLK15 variant, since cardiovascular defects occur in the hEDS population. The mice with the KLK15 variant showed changes in the mitral and aortic valves, whereas the healthy mice without the variant had no detectable valve defects.

Conclusion

The Norris Lab studied a large family with hEDS and found a rare variant in the KLK15 gene. They also found this variant in a smaller family with hEDS. Further research showed more rare variants in the KLK gene family among 197 hEDS patients compared to the general population. A mouse model further confirmed the role of the KLK15 variant in connective tissue, providing biological support beyond just genetic studies. This research helps us understand the disease better and will guide ongoing and future research directions.

Disclaimer: This blog is separate from my role as a postdoctoral fellow at the Medical University of South Carolina.