As you might guess, I’m keenly interested in the genetics of retinal diseases like retinitis pigmentosa and macular degeneration. It’s therefore a thrill when there’s an update to RetNet — the database of genes and loci causing retinal disease — that includes one of our recent discoveries.
For the last few years, we’ve been working with Steve Daiger, Sara Bowne, and Lori Sullivan at the University of Texas, Houston to find new genes for retinitis pigmentosa (RP), a retinal degenerative disorder affecting about 1 in 5,000 individuals in the United States. The disease usually manifests in childhood or adolescence with night blindness, followed by progressive loss of peripheral vision and eventually central vision.
RP is a Mendelian disorder (i.e. caused by mutations passed from one or both parents to a child) but is incredibly heterogeneous: it can be inherited in dominant, recessive, or X-linked fashion. About 20 genes have been linked to the dominant form, and if you screen them (e.g. with a capture panel) in a newly-diagnosed patient, you find the causal mutation about 50-75% of the time. Steve’s group has spent the last 20 years building a sample cohort of families in the other 25%.
As part of our collaboration, we sequenced the exomes of several individuals from a large dominant RP pedigree. It was so large that we actually treated it as two distinct families, because we thought there were two genes. But our variant analysis of the exome data revealed that there was one variant that was present in every affected, absent from every unaffected, and as-yet-unknown to dbSNP. A promising lead, but there were two issues:
- The variant was homozygous in one of the affected individuals, which is generally unexpected for rare dominant Mendelian disorders.
- The variant’s gene was hexokinase 1 (HK1), which catalyzes phosphorylation of glucose to glucose-6-phosphate and has no obvious connection to retina function.
The gene was highly expressed in the retina, which is consistent with many known RP genes. The final piece of evidence came from laborious screening of HK1‘s exons in hundreds of families from the Daiger cohort. That turned up a second family with the same exact disease-causing mutation. Our publication of HK1 last year established it as a new disease gene for dominant RP and suggests a new pathway (glycolysis) that may be involved in retinal disease.
Growth of Known Retinal Disease Genes
Here’s the latest content of RetNet, with numbers compared to the last release (end of 2014).
- 278 total retinal-disease genes have been mapped (up from 261).
- 238 have been identified at a DNA level (up from 221).
At least 25% of RetNet genes are associated with complex developmental and/or cerebellar diseases that include incidental retinal findings. One reason for their inclusion is that many also have mutations with ocular findings only. However, panel screening of these genes is likely to detect mutations with severe non-ocular consequences.
The First Noncoding-RNA Retinal Disease Gene
This release of RetNet includes the first entry of a non-coding RNA gene associated with retinal disease. Conte et al applied linkage mapping and exome sequencing of a five-generation British family with dominant retinal degeneration and bilateral iris coloboma (“holes in the iris”). They identified a variant in the seed region of MIR204, a micro-RNA gene at chr9q21.12, which segregated with disease.
Subsequent experimental work demonstrated that mir204 plays a role in ocular development and that the variant allele severely altered its targeting abilities. Very cool stuff.
The Award for Disease Diversity Goes to…
The PRPH2 at RetNet gene, which encodes peripherin (a protein in rod photoreceptor outer segments) was cloned in 1990. Over the last 25 years, mutations in that gene have been linked to:
- Dominant retinitis pigmentosa (accounts for 5% of cases);
- Dominant macular dystrophy;
- Dominant cone-rod dystrophy
- Dominant central areolar choroidal dystrophy
- Dominant adult vitelliform macular dystrophy
- Recessive Leber congenital amaurosis
It’s also been linked to a super-rare digenic form of retinal disease: heterozygous mutations in PRPH2 and another gene (ROM1) in the same individual can cause retinitis pigmentosa.
Other RetNet Highlights
Here are some of the other recent findings that made the latest release of RetNet which highlight the complexity of retinal disease genetics.
Syndromic Retinal Disease
Often, retinal disease manifests as one of several symptoms in a rare genetic syndrome. For example:
- HGSNAT (8p11.21). Recessive HGSNAT mutations cause non-syndromic RP but other mutations cause Sanfilippo syndrome, a mucopolysaccharidosis with central nervous system degeneration and retinal dystrophy. The protein, lysosomal N-acetyltransferase, acetylates heparin and heparan sulfate.
- IFT172 (2p33.3). Recessive mutations in IFT172 cause a range of disorders including non-syndromic RP, and Bardet-Biedl, Jeune or Mainzer-Saladino syndromes. The protein is involved in intraflagellar transport and, as with the other IFT proteins, is a cause of variable ciliopathies.
- LAMA1 (18p11.31-p11.23). Mutations in LAMA1 cause recessive Poretti-Boltshauser syndrome with variable developmental abnormalities of the brain and retina. The protein is a laminin which have critical roles in embryogenesis.
- NR2F1 (5q15). Mutations in NR2F1 cause dominant optic atrophy with intellectual disability and developmental delay, also known as Bosch-Boonstra optic atrophy. The protein is a nuclear receptor involved in optic nerve and cerebellar development.
- PNPLA6 (19p13.2). Recessive mutations in PNPLA6 cause variable disorders, such as Boucher-Neuhauser, Oliver-McFarlane or Gordon Holmes syndromes, involving spinocerebellar ataxia, hypogonadism and chorioretinal dystrophy. The protein is involved in phosphatidylcholine metabolism.
Genes Linked to Retinal Disease
Other genes updated in this release of RetNet are linked primarily to retinal disease, rather than a constellation of symptoms. For example:
- DHX38 (16q22.2). A homozygous missense mutation in DHX38 causes recessive RP and macular coloboma in a consanguineous family. The protein is a pre-RNA splicing helicase.
- DRAM2 (1p13.3). DRAM2 mutations in several families cause recessive, adult-onset retinal dystrophy with early macular involvement. DRAM2 codes for a transmembrane protein which initiates autophagy with a role in photoreceptor disc recycling.
- KIZ (20p11.23). Mutations in KIZ cause recessive rod cone dystrophy and may account for 1% of recessive RP patients in some populations. The protein is centrosome-associated as are other ciliopathy proteins.
- RDH11 (14q24.1). RDH11 mutations cause recessive RP with developmental abnormalities in an Italian-American family. The protein plays a role in oxidizing 11-cis-retinol to 11-cis-retinal in the visual cycle.
- TTLL5 (14q24.3). Mutations in TTLL5 cause recessive cone and cone-rod dystrophies. The protein is a tubulin glutamylase found in photoreceptor cilia and sperm flagella.
The diversity of phenotypes, pathways, and gene functions associated with retinal disease continues to astonish me. As usual, we’ve made remarkable progress but there’s more work to do.