Report on visit to Dr. Mignot’s lab (Stanford University) to discuss KLS research

I visited Stanford University on January 9, 2018 to discuss KLS research in the Mignot lab.  I met with Dr. Ling Lin, Senior Research Scientist, and Dr. Aditya Ambatyi, Postdoctoral Researcher, who are currently involved in the ongoing KLS research.  Dr. Lin has been a valuable contributor to the Mignot lab for over 15 years and Dr. Ambatyi, an expert in bioinformatics, genomics and immunology, joined the lab about 2 years ago.  Dr. Mignot was away traveling.

The KLS research in the Mignot lab at Stanford University has taken several experimental approaches.  The diagram below of the “Central Dogma of Life” should help to understand these approaches.  The diagram outlines the basic flow of biological information from our genes (encoded in the DNA in our chromosomes), to the ‘messenger’ molecule RNA, and then to proteins which carry out the myriad functions in our body and manifest our traits.

Experimental approach:


One challenge in studying KLS has been that no medical test has yet identified a specific abnormality or marker in individuals with KLS, which would usually be a starting point to begin such biomedical research studies.  Over the past decades, several hypotheses have been generated about the cause of KLS, but no solid scientific finding has emerged.

Dr. Mignot’s lab has approached this scientific problem with a three prong strategy probing each of the major biological steps depicted above.  These experimental techniques, known as (1) GWAS, (2) exome and (3) proteomics studies, are explained below with an update on the state of these exciting studies.

  • The first experimental approach is known as GWAS (“Genome Wide Association Studies”), a technique that has successfully been used to identify genetic changes in DNA associated with many other diseases. As reported by Dr. Mignot at the SLEEP 2017 medical conference in Boston and in a report to the KLS Foundation, there is increasing confidence in the lab’s finding of a change in the DNA in a genomic region in individuals with KLS as compared to healthy controls (this is called a ‘genetic polymorphism’).

We reviewed the results of the latest KLS GWAS data.  The lab is focusing on one ‘genetic polymorphism’ in the DNA located near a gene called TRANK1.  This finding is based on an analysis of about 600 samples of DNA extracted from blood contributed by individuals with KLS during the past 15 plus years.  An additional 100 KLS DNA samples have more recently been analyzed, but the data not yet merged.  In addition to the TRANK1 gene, this same region of DNA in the genome contains several other functional genes and any connection with KLS requires further study.  The lab has also been analyzing specific DNA changes in one of the genetic polymorphisms and comparing these changes to medical symptoms in KLS (as reported by individuals in the KLS questionnaire and in medical records).  Several noteworthy correlations between DNA changes and KLS medical symptoms have been found.

  • The second experimental approach is called exome sequencing. The exome is a much smaller part of the genome formed by DNA (and subsequently RNA) which encodes for proteins.  Therefore, determining the sequence of the exome is a technique to determine the make-up of all of our protein-coding genes.  One can think of it as an effort to identify disease-causing genetic variants within the approximately 1% of the human genome which specifically codes for proteins.

The lab is looking for changes in the ‘exome’ of individuals with KLS as compared to healthy controls.  More specifically, the focus has been on exome sequencing in those KLS families with more than one individual diagnosed with KLS.  Comparison of the exome DNA from multiple members of the same family can identify further biological changes associated with KLS.  The sequencing has been performed but the results not yet fully analyzed.

  • A third experimental approach is called proteomics, which involves looking directly at the identity and amount of the various proteins in our body.

Dr. Mignot is collaborating with a lab that can analyze 1,300 (soon to be 5,000) proteins in various clinical samples, including blood and CSF (‘cerebral spinal fluid’ drawn from a spinal tap).  I reviewed with Aditya the results of a study of proteins in CSF samples of KLS subjects as compared to healthy controls.  Of approximately 1,300 proteins analyzed, different amounts were found in about 100 proteins.  The most significant differences cluster in proteins that are known to be involved in cells that fight diseases.  We discussed numerous clinical implications of this finding.

Overall, it was a very exciting visit to review the experimental data and discuss interpretations of the research results to date.  These multiple experimental approaches are leading to a quantum leap in having discreet experimental findings to pursue a real understanding of the cause of KLS.  The clinical research samples donated by KLS individuals and families which have been collected, maintained and banked at Stanford will continue to be a very valuable KLS research resource.  Expeditious dissemination of these experimental findings will encourage other labs to collaborate and will bolster complementary KLS research studies.  These studies will inevitably lead to objective KLS clinical diagnoses and rational treatments.

Neal M FarberPhD
KLS Foundation Board member

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