About

Radha Ayyagari is a Professor In Residence in the Department of Ophthalmology at UC San Diego. Her research focuses on unraveling the molecular pathology of retinal degeneration through advanced genomic techniques such as single cell genomics and epigenome analysis. She has contributed significantly to understanding the molecular mechanisms underlying various retinal diseases, including retinitis pigmentosa, macular degeneration, and hereditary retinal degenerations. Her work involves investigating genetic variants, molecular pathways, and cellular processes that lead to retinal deterioration, with the aim of developing targeted treatments. Dr. Ayyagari has been the principal investigator on multiple NIH-funded projects and has published extensively on the genetic and molecular basis of retinal diseases, including studies on the role of specific gene variants and cellular mechanisms in retinal degeneration.

Research topics

• Biology
• Genetics
• Evolutionary biology
• Demography

Selected publications

• De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa

  Nature Genetics · 2026-01-01 · 6 citations

  articleOpen access

  Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration. De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

  PublisherOA PDFDOI

• Multi-omic analysis of photoreceptor alterations during early-onset retinal degeneration in <i> Mfrp ^-/- </i> mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-02

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Loss-of-function mutations in the membrane frizzled-related protein ( MFRP ) gene are associated with autosomal recessive ocular disorders such as nanophthalmos, posterior microphthalmia, and retinitis pigmentosa, yet the molecular mechanisms underlying MFRP -related retinal degeneration remain poorly defined. To investigate these mechanisms, we generated and characterized Mfrp -/- mice and conducted an integrated multi-omic analysis to map the onset and progression of transcriptional changes during retinal degeneration. Using longitudinal in vivo imaging, histological and immunohistochemical analysis, qRT-PCR, single-nucleus RNA sequencing (snRNA-seq), snATAC seq (single-nucleus Assay for Transposase-Accessible Chromatin using sequencing) and spatial transcriptomics (GeoMx DSP), we identified early and progressive photoreceptor loss in Mfrp -/- mice, beginning by 28d. Retinal thinning and autofluorescent deposits in Mfrp -/- mice were accompanied by decreased expression of rod and cone opsins. Transcriptomic profiling by snRNA-seq revealed distinct, photoreceptor-specific gene expression changes, including early upregulation of inflammatory and stress-related genes and later downregulation of genes involved in chromatin remodeling, synaptic function, and neurodevelopment. Spatial transcriptomic analysis of the outer nuclear layer (ONL) revealed disruptions in mitochondrial function, mTORC1 signaling, and G protein–coupled receptor pathways. These findings define a temporally and spatially coordinated program of degeneration triggered by Mfrp loss and demonstrate that Mfrp is required for the maintenance of photoreceptor integrity and gene regulatory homeostasis during retinal development. Our work establishes Mfrp -/- mice as a robust model for dissecting photoreceptor vulnerability and provides a transcriptomic atlas of disease progression with potential relevance for therapeutic development in MFRP -associated retinal dystrophies.

  PublisherOA PDFDOI

• Advancing Equity in Diabetes Prevention for Both Black and Hispanic Women: An Executive Summary of Lessons Learned and Action Steps

  AJPM Focus · 2025-01-10 · 1 citations

  articleOpen access

  Introduction: This report presents challenges, lessons learned, and action steps for healthcare organizations referring to or delivering the National Diabetes Prevention Program lifestyle change program to create culturally responsive Type 2 diabetes prevention strategies for disproportionately affected populations, specifically Black and Hispanic women with prediabetes. Methods: The American College of Preventive Medicine, American Medical Association, and Black Women's Health Imperative identified healthcare organizations to build provider capacity to screen, test, and refer disproportionately affected populations to the National Diabetes Prevention Program. Sites provided data on participants screened, referred, and enrolled and qualitative reporting on barriers and facilitators to enrollment over a 36-month period. Key informant interviews were conducted with organizations implementing the National Diabetes Prevention Program to reduce prevalence of prediabetes in disproportionately affected populations, integrating thematic analysis to identify unique strategies. Results: Healthcare organizations play a critical role in advancing equity at every level of diabetes prevention, including screening, testing, and referring participants to the National Diabetes Prevention Program lifestyle change program; engaging and retaining participants in the program; and screening and addressing social needs. Conclusions: Healthcare organizations reduce disparities and advance health equity for disproportionately affected populations by cultivating program champions, engaging in community outreach, and advocating for systemic changes to increase accessibility.

  PublisherOA PDFDOI

• A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma

  UNC Libraries · 2025-02-01

  articleOpen access
  PublisherDOI

• De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa

  medRxiv · 2025-01-06 · 13 citations

  preprintOpen access

  ABSTRACT The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ∼30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent de novo variants in the U4 RNA, transcribed from the RNU4-2 gene, and in at least two other RNU genes were discovered to cause neurodevelopmental disorder. We detected inherited and de novo heterozygous variants in RNU4-2 (n.18_19insA and n.56T&gt;C) and in four out of the five RNU6 paralogues (n.55_56insG and n.56_57insG) in 135 individuals from 62 families with non-syndromic retinitis pigmentosa (RP), a rare form of hereditary blindness. We show that these variants are recurrent among RP families and invariably cluster in close proximity within the three-way junction (between stem-I, the 5’ stem-loop and stem-II) of the U4/U6 duplex, affecting its natural conformation. Interestingly, this region binds to numerous splicing factors of the tri-snRNP complex including PRPF3, PRPF8 and PRPF31, previously associated with RP as well. The U4 and U6 variants identified seem to affect snRNP biogenesis, namely the U4/U6 di-snRNP, which is an assembly intermediate of the tri-snRNP. Based on the number of positive cases observed, deleterious variants in RNU4-2 and in RNU6 paralogues could be a significant cause of isolated or dominant RP, accounting for up to 1.2% of all undiagnosed RP cases. This study highlights the role of non-coding genes in rare Mendelian disorders and uncovers pleiotropy in RNU4-2 , where different variants underlie neurodevelopmental disorder and RP.

  PublisherOA PDFDOI

• Ablation of Htra1 leads to sub-RPE deposits and photoreceptor abnormalities

  JCI Insight · 2025-02-10 · 2 citations

  articleOpen accessSenior author

  The high-temperature requirement A1 (HTRA1), a serine protease, has been demonstrated to play a pivotal role in the extracellular matrix (ECM) and has been reported to be associated with the pathogenesis of age-related macular degeneration (AMD). To delineate its role in the retina, the phenotype of homozygous Htra1-KO (Htra1-/-) mice was characterized to examine the effect of Htra1 loss on the retina and retinal pigment epithelium (RPE) with age. The ablation of Htra1 led to a significant reduction in rod and cone photoreceptor function, primary cone abnormalities followed by rods, and atrophy in the RPE compared with WT mice. Ultrastructural analysis of Htra1-/- mice revealed RPE and Bruch's membrane (BM) abnormalities, including the presence of sub-RPE deposits at 5 months (m) that progressed with age accompanied by increased severity of pathology. Htra1-/- mice also displayed alterations in key markers for inflammation, autophagy, and lipid metabolism in the retina. These results highlight the crucial role of HTRA1 in the retina and RPE. Furthermore, this study allows for the Htra1-/- mouse model to be utilized for deciphering mechanisms that lead to sub-RPE deposit phenotypes including AMD.

  PublisherOA PDFDOI

• MFRP in Early Onset Retinal Degeneration: Clinical and Molecular Perspectives

  Advances in experimental medicine and biology · 2025-01-01 · 1 citations

  reviewOpen accessSenior author
  PublisherOA PDFDOI

• Current and Future Directions in Developing Effective Treatments for <i>PRPH2-</i>Associated Retinal Diseases: A Workshop Report

  Translational Vision Science & Technology · 2024-10-09 · 4 citations

  articleOpen access1st author

  Purpose and Methods: A workshop of affected individuals and their families, clinicians, researchers, and industry representatives was convened in March 2023 to define the knowledge landscape of peripherin 2 (PRPH2) biology and identify challenges and opportunities towards developing PRPH2-associated inherited retinal disease (IRD) treatments. Results: The results of an online survey and presentations from affected individuals and their family members revealed disease characteristics and impacts on daily living. Scientific sessions highlighted the significant heterogeneity in clinical presentation of PRPH2-related retinopathy; PRPH2's crucial function in rod and cone outer segment formation and maintenance; the usefulness of existing animal and cellular models for understanding disease pathophysiology; and possible therapeutic approaches for autosomal dominant PRPH2-associated IRDs, including gene-specific therapies and gene-agnostic approaches. Priority gaps identified by the workshop included having a more complete understanding of PRPH2's fundamental biology and factors contributing to PRPH2-related disease phenotypic diversity, establishing genotype-phenotype correlations, and creating additional models to probe the functional consequences of PRPH2 variants and to test therapies. Additionally, a natural history study involving a large number of participants is required to more fully characterize PRPH2-related disease progression, aiding in interventional clinical trial design. Conclusions: Because PRPH2-associated IRDs are rare, maximizing opportunities for communication and collaboration among stakeholders, such as that provided by the workshop, is crucial to overcome the challenges to developing effective treatments and improve the lives of affected individuals. Translational Relevance: Fostering communication among stakeholders to identify knowledge gaps, therapeutic challenges, and potential opportunities toward developing effective treatments for PRPH2-related IRDs.

  PublisherOA PDFDOI

• Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression

  The American Journal of Human Genetics · 2024-08-26 · 6 citations

  articleOpen accessSenior author

  Genome analysis of individuals affected by retinitis pigmentosa (RP) identified two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]), in individuals of South Asian and African ancestry, respectively. Genotypes included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations. Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted. Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity. Nanopore sequencing confirmed the lower transcription of the TMEM216 c.-69G>T allele in blood-derived RNA from a heterozygous carrier, and reduced expression was further recapitulated by qPCR, using both leukocytes-derived RNA of c.-69G>T homozygotes and total RNA from genome-edited hTERT-RPE1 cells carrying homozygous TMEM216 c.-69G>A. In conclusion, these variants explain a significant proportion of unsolved cases, specifically in individuals of African ancestry, suggesting that reduced TMEM216 expression might lead to abnormal ciliogenesis and photoreceptor degeneration.

  PublisherOA PDFDOI

• Performance of Polygenic Risk Scores for Primary Open-Angle Glaucoma in Populations of African Descent

  JAMA Ophthalmology · 2024-11-14 · 4 citations

  letterOpen access

  Importance: Primary open-angle glaucoma (POAG) polygenic risk scores (PRSs) continue to be evaluated in primarily European-ancestry populations despite higher prevalence and worse outcomes in African-ancestry populations. Objective: To evaluate how established POAG PRSs perform in African-ancestry samples from the Genetics in Glaucoma Patients of African Descent (GIGA), Genetics of Glaucoma in Individuals of African Descent (GGLAD), and Million Veteran Program (MVP) datasets and compare these with European-ancestry samples. Design, Setting, and Participants: This was a multicenter, cross-sectional study of POAG cases and controls from Tanzania, South Africa, Nigeria, Ghana, and the US. Included were individuals of African descent from South Africa and Tanzania from the GIGA dataset; individuals of African descent from Ghana, Nigeria, and the US from the GGLAD dataset; and individuals of African or European descent from the US in the MVP dataset. Data were analyzed from January 2022 to July 2023. Exposures: Three PRSs derived from large meta-analyses of European and Asian populations, namely Gharahkhani et al (Gharahkhani PRS), Han et al (Han PRS), and Craig et al (Craig PRS). Main Outcomes and Measures: Odds ratios (ORs) for POAG risk stratification comparing the highest and lowest quintiles; area under the receiver operating characteristic curve (AUROC), and liability coefficient of determination (R2) for the addition of PRS to a baseline of age, sex, and first 5 principal components. Results: A total of 11 673 cases and 66 432 controls were included in this study across 7 ancestral groups. Mean (SD) age of the total participants was 76.9 (8.7) years, with 74 304 males (95.1%). The following were included in each dataset: GIGA (663 cases, 476 controls), GGLAD (1471 cases, 1482 controls), and MVP (9559 cases, 64 474 controls). Increases in ORs were found for the highest POAG risk quintile ranging from an OR of 1.68 (95% CI, 1.17-2.43) in Ghanaians to 7.05 (95% CI, 2.73-19.6) in the South African multiple ancestry group (which derives from at least 5 distinct ancestral groups: Khoisan, Bantus, Europeans, Indians, and Southeast Asians) with the Gharahkhani PRS. The Han PRS showed OR increases for the highest POAG risk quintile ranging from 2.27 (95% CI, 1.49-3.47) in African American individuals in the GGLAD dataset to 7.24 (95% CI, 6.47-8.12) in Europeans. The Craig PRS predicted OR increases in the highest quintile for all groups ranging from 1.51 (95% CI, 1.05-2.18) in Ghanaians to 6.31 (95% CI, 5.67-7.04) in Europeans. However, AUROC and R2 increases above baseline were lower for all African-ancestry compared with European-ancestry groups in the 3 tested PRSs. Conclusions and Relevance: In this cross-sectional study, despite some improvements in OR-based risk stratification using the Gharahkhani PRSs, Han PRSs, and Craig PRSs, consistently lower improvements in AUROC and R2 for African-ancestry compared with European-ancestry groups highlight the need for risk prediction models tailored to diverse populations.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01EY02123704

  NIH · $601k · 2016

• NIH Grant R01EY013198

  NIH · $4.0M · 2013

• NIH Grant R01EY021237

  NIH · $5.0M · 2022

• Vision Biostatistics

  NIH · $17.7M · 2023–2028

Frequent coauthors

• Sheikh Riazuddin

  Johns Hopkins University

  217 shared

• Pooja Biswas

  University of San Diego

  141 shared

• J. Fielding Hejtmancik

  National Eye Institute

  95 shared

• Muhammad Asif Naeem

  University of the Punjab

  84 shared

• Paul A. Sieving

  National Eye Institute

  83 shared

• Venkata Ramana Murthy Chavali

  Penn Presbyterian Medical Center

  75 shared

• Shyamanga Borooah

  Jacobs (United States)

  72 shared

• John Suk

  Myriad Genetics

  61 shared

Education

• Ph.D., Ophthalmology

  University of California, San Diego

  1995

• M.D., Medicine

  University of California, San Diego

  1991

• B.A., Biology

  University of California, San Diego

  1987