Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are the most common hereditary diseases causing visual impairment and can lead to childhood blindness. It was previously hypothesised that LCA and RP might be caused by mutations in the same gene, given their substantial clinical similarities. Dr. Robert Koenekoop’s team recently discovered a gene that causes LCA and RP. Up until now 15 genes have been identified as being involved in LCA, but not causing the disease. This new discovery identified SPATA7 (spermatogenesis associated protein 7), a gene mutation disrupting protein transport between the endoplasmic reticulum and the Golgi apparatus. As all proteins travel via this pathway, SPATA7 mutations affect many aspects of vision.
“Until now we were not aware that this cellular mechanism played a role in LCA or any other eye disease. This is a very important step that opens up a number of new research avenues, particularly in our understanding of the specific cellular processes involved in blindness. This finding also increases the number of potential therapeutic targets and therefore the chances of finding a treatment” explained Dr. Koenekoop.
Homozygosity mapping was utilized to confine critical sections of the LCA3 locus. Using direct Sanger sequencing of all genes within this section, homozygous nonsense mutation in the SPATA7 genes were identified, along with three other loss-of-function mutations were consequently discovered in LCA and juvenile RP patients. Unaffected family members of LCA and RP participants were either heterozygous or did not carry the mutation. These findings provide a promising correlation between the severity of mutant alleles in SPATA7 and the resulting clinical phenotype, LCA or RP. SPATA7 was also examined in mature mouse retina, they found it expressed in multiple retinal layers. Patients with a specific genetic type of LCA were identified to have present retinal cels, though not functional for vision. This observation supports research into genetic therapies to combat mutant changes in SPATA7.
“Until now we were not aware that this cellular mechanism played a role in LCA or any other eye disease. This is a very important step that opens up a number of new research avenues, particularly in our understanding of the specific cellular processes involved in blindness. This finding also increases the number of potential therapeutic targets and therefore the chances of finding a treatment” explained Dr. Koenekoop.
Homozygosity mapping was utilized to confine critical sections of the LCA3 locus. Using direct Sanger sequencing of all genes within this section, homozygous nonsense mutation in the SPATA7 genes were identified, along with three other loss-of-function mutations were consequently discovered in LCA and juvenile RP patients. Unaffected family members of LCA and RP participants were either heterozygous or did not carry the mutation. These findings provide a promising correlation between the severity of mutant alleles in SPATA7 and the resulting clinical phenotype, LCA or RP. SPATA7 was also examined in mature mouse retina, they found it expressed in multiple retinal layers. Patients with a specific genetic type of LCA were identified to have present retinal cels, though not functional for vision. This observation supports research into genetic therapies to combat mutant changes in SPATA7.
Figure 1. Color Photographs of the Retinas of Two RP Patients with SPATA7 Mutations
Student ID: s4186886
Reference.
Wang, H., den Hollander, A., Moayedi, Y., Abulimiti, A., Li, Y., Collin, R., Hoyn, C,. Lopez, I., Bray, M,. Lewis, R,. Lupske, J,. Mardon, G,. Koenkoop, R,. & Chen, R. 2009. ‘Mutations in SPATA7 cause Leber Congenital Amaurosis and Juvenille Retinitis Pigmentosa’. The American Journal of Human Genetics, 84(3), 380-387.
