For all descendants of Ervin and Ellen Slocum.
This page is maintained by Paul Martz (email me: skewmatrix '@' gmail.com)
I had three tests to determine our family mutation. Here they are, most recent and most important first:
Confirmation test. If you only look at one thing on this page, look at this XLRP test with positive results from 01/2016. This test identifies our family's RP mutation as RPGR ORF15, more specifically, c.2763_2764delGG.
These are less important than the test above, so you can pretty much ignore them.
05/2013 XLRP test. This was my second test, looking for a needle in a haystack. It looked at RP2 and RPGR, but came back negative because it failed to look for any RPGR ORF15 mutations.
Here's my first attempt to find the mutation, an ADRP test, 12/2010. We never intended to test for ADRP and this was a lab mix-up. But it identified some "potentially pathenogenic" variations. ADRP test, p2 of 4. ADRP test, p3 of 4. ADRP test, p4 of 4.
RPGR is both a protein, and a segment of the x-chromosome that codes for that protein. Our DNA contains a mutation in that section, and our RPGR protein is malformed and probably non-functional. The RPGR protein is present in the top-most photoreceptor cell layer of the retina and plays a role in photoreceptor function and health. Because our RPGR is defective, photoreceptor cells slowly die over time, starting with the rod cells in the periphery, and eventually the cone cells responsible for central vision.
There is currently no cure or treatment. However, knowing our mutation, there are some positive things we can do today, and we are also watching research that is specifically applicable to our mutation. Continue reading for detailed information.
A man has one x and one y chromosome. A woman has two x chromosomes. A man with our RP will always show symptoms, but a woman could be a carrier with no symptoms, or might develop symptoms later in life. If a man with our RP has children, he never passes it to sons, but always passes it to daughters. A woman with our RP, either a carrier or with symptoms, will have a 50-50 chance of passing it to her children, depending on which one of her two x chromosomes randomly get used at fertilization time.
An example from our family tree: Ellen Slocum was a symptomatic carrier of RP. She married Ervin Slocum and had 11 children in the mid- to late-1800s. Six of the children inherited RP and five did not. This is roughly 50%. Some of the affected children were male, some were female. It was a coin toss for each child.
Here's another example: Sherman Slocum had RP (he was one of Ellen's six affected children). He had four children, two sons and two daughters. The two sons did not inherit RP because affected men never pass it to their sons. However, both daughters inherited RP (and consequently passed it to some of their children).
For more information, here's an article on x-linked inheritance.
Now that we know our mutation, we can identify RP research that will be applicable to us. Any treatment that regenerates lost photoreceptor cells or preserves photoreceptor cells, any research that causes the retina to function in the absence of photoreceptor cells, and any gene therapy that targets our mutation, are all of particular interest to us.
FFB 2015 top 10 research projects.
Optogenetics clinical trial and another article about the optogenetics trial. Optogenetics causes the retina to function without photoreceptor cells. It does this by modifying the DNA of the cells below the photoreceptor layer in such a way that those cells become light sensitive. The expectation is that this will provide less than perfect monochrome vision, but should be superior to (for example) the Argus II implant from SecondSight.
Acucela licenses technology from University of Mancehster A similar technique to RetroSense, but Acucela is using rhodopsin as the protein, a protein normally found in human photoreceptor cells. In theory, using a human protein DNA segment makes this technique somewhat safer than using algae DNA. But both techniques will probably work just as well.
Gene Therapy Targeting RPGR
All RPGR gene therapy teams appear to currently be working with animal models and expect 3-5 years before human clinical trials. I'm writing this in March 2016, so maybe the year 2020 for Phase 1 clinical trials.
As a worst-case timeline for gene therapy, consider that LCA gene therapy still lacks FDA-approval, even though it was proven on animal models in 2001. FDA approval sought for LCA gene therapy.
AGTC. The fact that a for-profit company is developing an RPGR gene therapy product is very promising.
RPGR ORF15 Gene Therapy (Mass Eye and Ear) Mass Eye and Ear gene therapy article. The lead investigator is Dr. Basil Pawlyk [email protected] They are working with animal models of our RPGR mutation and finding ways to remove the defective part of the gene sequence.
UPenn Gene Therapy This group is also working on gene therapy using animal models of our RPGR mutation. One UPenn gene therapy article and another UPenn gene therapy article. The lead investigator is Dr. William A. Beltran [email protected]
General stem Cell info. Article about growing cone photoreceptors from Canadian researchers.
jCyte In clinical trials to demonstrate the neuroprotective effect of stem cells. These guys are not growing photoreceptors. Lead researcher: Dr Henry Klassen, UC-Irvine jCyte / UC-Irvine stem cell video from October 2014. Clinical trial web page.
ReNeuron Injection of juman retinal progenitor stem cells with the intent of growing new photoreceptors. Currently in Phase 1 clinical trial. Phase 1 should be complete in the March-September 2017 timeframe. Clinical Trial page. Lead researcher Eric Pierce at Mass Eye and Ear.
I'll mention the SCOTS trial in Florida just for completeness, but I'm skeptical of them for a number of reasons.
Detailed Genetic Information
The RPGR ORF15 c.2763_2764delGG mutation was first identified in the year 2000. Original discovery paper from 2000. If you can't get the full paper but you want it, email me. It's not very meaningful unless you're a geneticist. In Vervoort's paper, our mutation is listed in Table 1 as sample 43, and uses a different notation: g.ORF15+1010_1011delGG. There is an MS Word files that lists all known RPGR mutations and uses both nomenclatures for our mutation.
What does "RPGR ORF15 c.2763_2764delGG" mean? Our mutation is on a section of the x-chromosome that codes for the RPGR protein (Retinitis Pigmentosa GTPase Regulator). "ORF15" is the exon. I think it stand for "open reading frame", which is explained in this highly technical online genetics textbook. I just think of "ORF15" as a smaller part of the RPGR segment. I don't know what the "c." is, so don't ask me. The DNA is composed of several base pairs that look like rungs on a ladder. Each pair has a number. Our mutation is a deletion of two pairs numbered 2763 and 2764. The "del" indicates a deletion, the pairs are missing. The final part, "GG" indicates the nucleotides that the pairs would code for if they were present. In this case, both of the missing pairs code for Guanine.The protein RPGR has something to do with photoreceptor ciliary function, and most likely regulates traffic of molecules between the inside and outside of a photoreceptor. I get the impression the function of RPGR isn't fully understood, and how the mutated RPGR causes RP and results in photoreceptor death is also not fully understood.
Here are a few online references: Wikipedia genetic code article Genetics Home Reference article on RPGR Guanine, adenine, cytosine, and thymine are the four DNA nucleotides that code for the 20 amino acid building blocks of all proteins.
Each rung in the DNA ladder codes for one of the four nucleotides. Groups of three nucleotides code for one of the 20 amino acids, which are the building blocks of RPGR and other proteins. Each group of three nucleotides is called an amino acid frame. When a deletion mutation occurs, the frame is now off (in our case by two rungs), and this is called a frameshift error. As a result, all subsequent amino acid frames code for the wrong amino acids. This is why deletion mutations are typically severe and symptomatic. Most are so severe that they result in early death or miscarriage. But because RPGR is not critical to life, we survive, with our mutation intact.