A Family’s Inheritance — #GeneOTW with CAPN5

For most expectant parents, part of the fun is wondering which traits will get passed down to your children. Will they have their father’s nose?  Their mother’s eyes?

For one Iowa family, there’s a different trait to worry about.  Sixty-one members of Jerry Jackson’s family1 have been diagnosed with ADNIV (autosomal dominant neovascular inflammatory vitreoretinopathy), an extremely rare genetic disease that eventually leads to blindness.  Jackson himself started getting vision problems in his 20s, and when a cousin developed similar symptoms, doctors began suspecting a genetic cause.  Eventually, the genetic mutation was traced back through generations of the family’s Scottish ancestry.2  Today, at 68 years old, Jerry Jackson is completely blind.3  Both his daughters were diagnosed with ADNIV,4 and since it’s an autosomal dominant disorder, all his grandchildren have a 50% chance of becoming blind.  Unfortunately, much remains unknown about the disease.

An autoimmune disorder, ADNIV causes inflammation and bleeding in the eye, and is characterized by progressive stages that mimic other eye diseases.  This means that studying ADNIV could help with other (more common) disorders, but for ADNIV patients, it also means that they pretty much experience a mash-up of multiple horrible diseases:5

  • Stage I: mimics autoimmune, non-infectious uveitis (inflammation of the middle vascular layer of the eye).
  • Stage II: like in retinitis pigmentosa, photoreceptors degenerate, which causes vision loss.
  • Stage III: similar to proliferative diabetic retinopathy.  Blood vessels proliferate in the eye, which clouds vision, can lead to bleeding, and ultimately damages the retina.
  • Stage IV: as in proliferative vitreoretinopathy, formation of excess fibrous connective tissue (fibrosis, as seen in scarring) can cause retinal detachment.
  • Stage V: continuation of all the symptoms above (e.g. inflammation, intraocular hemorrhage, fibrosis) eventually leads to complete blindness.
Images of normal and ADNIV retinas.

Images of normal and ADNIV retinas. The arrow points to pigmentary degeneration that’s characteristic of both Stage II (of ADNIV) and Retinitis Pigmentosa. [Source: Mahajan et al. (2012) PLoS Genet 8(10):e1003001.]

In 2012, scientists finally identified the genetic mutation that causes ADNIV.  Amongst three families with ADNIV (including Jerry Jackson’s), all patients had a mutation in the CAPN5 gene.6 CAPN5 encodes the protein Calpain-5, a calcium-activated protease with a currently unknown physiological function.

In general, the Calpain family proteins are known to target multiple intracellular proteins and pathways, and unlike other proteases, are not involved in protein degradation.  Instead, they can modulate the structure (and thus activity) of their target substrates.4  Being highly conserved enzymes, calpains are found in most eukaryotes, and defects in these proteins can have severe effects including lethality.7 Given that calpains typically have diverse target substrates, it may be unsurprising that CAPN5 has also been implicated in other diseases like endometriosis and polycystic ovary syndrome.89 After all, it is expressed in a variety of tissues including the colon, kidney, liver, trachea, uterus, eye, and brain.10  Still, we don’t know which proteins CAPN5 interacts with, in any of these tissues.

Even so, scientists have found a way to potentially treat ADNIV.  Instead of targeting specific signaling pathways (since we don’t know them), doctors are taking the general approach of treating inflammation, and thus, its negative consequences.  Some ADNIV patients have already received an implant that continuously releases corticosteroids within the eye, which has been shown to reduce inflammation and neovascularization.11  The surgical implant works best when implemented early in disease progression, and while it’s too soon to tell, doctors are hopeful that it could slow vision loss, and perhaps even allow ADNIV patients to permanently retain central, if not peripheral, vision.12

 

No, these aren't abstract drawings.  They're diagrams of eyes from two ADNIV patients that received implants.

No, these aren’t abstract drawings… they’re diagrams of eyes from two ADNIV patients that received implants.  Note the pervasive presence of neovascularization, fibrosis, and areas of retinal detachment.  [Source: Tlucek et al. (2012) Clin Opthalmol 7:1093-8.]

Of course, this new treatment offers a considerable amount of hope to all ADNIV patients.  As for Jerry Jackson himself, he hasn’t let blindness disable him; he still works as a bicycle mechanic (in addition to his job at the grocery store), and enjoys long bicycle rides—on both a tandem bike, and occasionally, even solo!13 His 25-year-old granddaughter, Bobbi Boline, also has the ADNIV gene variant, but having seen her grandfather living a full life, has said, “I’m OK with it.”14  As Jackson’s daughter has said, “[Blindness] never stopped him from anything.  He just went and went and went.”15

 

To learn more about CAPN5, explore the gene report at BioGPS!

References:

  1. Mike Kilen. “Iowa family fights disease that has blinded 61 members.” USA Today. Retrieved 5 September 2014, from http://www.usatoday.com/story/news/nation/2013/06/16/iowa-family-fights-genetic-blindness/2429417/ []
  2. Engel, Meredith. “Iowa family hit hard by rare blindness gene.” NY Daily News. Retrieved on 3 September 2014, from http://www.nydailynews.com/life-style/health/iowa-family-hit-hard-rare-blindness-gene-article-1.1921863 []
  3. Engel, Meredith. “Iowa family hit hard by rare blindness gene.” NY Daily News. Retrieved on 3 September 2014, from http://www.nydailynews.com/life-style/health/iowa-family-hit-hard-rare-blindness-gene-article-1.1921863 []
  4. Mike Kilen. “Iowa family fights disease that has blinded 61 members.” USA Today. Retrieved 5 September 2014, from http://www.usatoday.com/story/news/nation/2013/06/16/iowa-family-fights-genetic-blindness/2429417/ []
  5. Mahajan VB, Skeie JM, Bassuk AG, Fingert JH, Braun TA, Daggett HT, Folk JC, Sheffield VC, Stone EM.  (2012) Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration. PLoS Genet 8(10):e1003001. []
  6. Mahajan VB, Skeie JM, Bassuk AG, Fingert JH, Braun TA, Daggett HT, Folk JC, Sheffield VC, Stone EM.  (2012) Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration. PLoS Genet 8(10):e1003001. []
  7. Sorimachi H, Hata S, Ono Y. (2011) Impact of genetic insights into calpain biology. J Biochem150(1):23-37. []
  8. Penna I, Du H, Ferriani R, Taylor HS. (2008) Calpain5 expression is decreased in endometriosis and regulated by HOXA10 in human endometrial cells. Mol Hum Reprod 14(10):613-8. []
  9. González A, Sáez ME, Aragón MJ, Galán JJ, Vettori P, Molina L, Rubio C, Real LM, Ruiz A, Ramírez-Lorca R. (2006) Specific haplotypes of the CALPAIN-5 gene are associated with polycystic ovary syndrome. Hum Reprod 21(4):943-51. []
  10. Mahajan VB, Skeie JM, Bassuk AG, Fingert JH, Braun TA, Daggett HT, Folk JC, Sheffield VC, Stone EM.  (2012) Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration. PLoS Genet 8(10):e1003001. []
  11. Tlucek PS, Folk JC, Sobol WM, Mahajan VB. (2013) Surgical management of fibrotic encapsulation of the fluocinolone acetonide implant in CAPN5-associated proliferative vitreoretinopathy. Clin Ophthalmol 7:1093-8. []
  12. Tlucek PS, Folk JC, Sobol WM, Mahajan VB. (2013) Surgical management of fibrotic encapsulation of the fluocinolone acetonide implant in CAPN5-associatedproliferative vitreoretinopathy. Clin Ophthalmol 7:1093-8. []
  13. Mike Kilen. “Iowa family fights disease that has blinded 61 members.” USA Today. Retrieved 5 September 2014, from http://www.usatoday.com/story/news/nation/2013/06/16/iowa-family-fights-genetic-blindness/2429417/ []
  14. Mike Kilen. “Iowa family fights disease that has blinded 61 members.” USA Today. Retrieved 5 September 2014, from http://www.usatoday.com/story/news/nation/2013/06/16/iowa-family-fights-genetic-blindness/2429417/ []
  15. Mike Kilen. “Iowa family fights disease that has blinded 61 members.” USA Today. Retrieved 5 September 2014, from http://www.usatoday.com/story/news/nation/2013/06/16/iowa-family-fights-genetic-blindness/2429417/ []

1 Comment

  1. Some of the writer’s information is incorrect. The only concern is that when this blog pops up, people trying to learn about the disease get incorrect information. Most people cannot separate fact from fiction on the internet and they don’t often check sources to validate the information they cite.

    Both mistakes cited below (and there are more) contained the correct information in the articles listed by the author. Ms. Lau, in the first instance, cited numbers from a story that was over a year old. She had even read and cited the source that had the correct information, but used the outdated instead. The second instance was misconstrued and incorrect.

    1) “Sixty-one members of Jerry Jackson’s family1 have been diagnosed with ADNIV…” This is old data. The writer even cited one of the sources that had – at that time – the most accurate information. People magazine reported on 28.Aug.2014(http://www.people.com/article/heroes-jackson-family-genetic-blindness) AND
    New York Daily News reported the following day, 29.Aug.14 (http://www.nydailynews.com/life-style/health/iowa-family-hit-hard-rare-blindness-gene-article-1.1921863) that 84 of approximately 123 known cases are in Jerry’s bloodline. In fact, the current and exact information is: 88 or the 126 known cases of ADNIV are in the Shearer ancestry, of which Jerry and his family are descendants (www.ADNIV.com)

    2) “…and enjoys long bicycle rides—on both a tandem bike, and occasionally, even solo!13” The source actually reads “He even took a solo ride a few years ago, following the sound of a card rattling in the spokes on his wife’s bike.” He only rode solo once, many years ago, which is a far cry from occasionally riding solo to this day.

    If Melissa Lau wants the real story on ADNIV, all clinical information can be found in papers authored by Dr. Vinit Mahajan and Dr. James C. Folk. Current information about the number of descendants in Jerry’s ancestries, as well as the other ancestry (surname) who have ADNIV, can now be found at http://www.ADNIV.com (a site managed and written by person who knows Jerry and his family personally).

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