# Cellular and Molecular Genetics of Keratoconus

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2020 · $435,422

## Abstract

ABSTRACT
 Our long term goal is to identify and characterize genetic mutations involved in the pathogenesis of
keratoconus (KC). KC is a bilateral, asymmetric corneal degeneration characterized by localized thinning and
protrusion of the thinned cornea. KC leads to high myopia, irregular astigmatism, and cornea scarring.
Although genetic factors contribute to KC pathogenesis, its genetic causes remain to be identified. Only
mutations in the VSX1 and MIR184 genes are known to cause KC, but they account for <10% KC cases. KC is
typically inherited through autosomal dominant patterns, though autosomal recessive patterns have been
reported. It affects males and females similarly and is detected in all ethnic groups worldwide. Our productive
collaborations with others amassing DNA samples from more than 600 KC individuals and their families have
led to the identification of KC-segregating mutations in three genes, including PPIP5K2 (diphosphoinositol
pentakisphosphate kinase 2). PPIP5K2 encodes a bifunctional kinase and phosphatase with high affinity to
InsP5 / 5-InsP7 and PtdIns(3,4,5)P3 respectively. In two multi-generation families with multiple affected
individuals, we have identified two heterozygous mutations affecting amino acids located in the
polyphosphoinositide binding domain (PBD) of PPIP5K2. PPIP5K2 is highly expressed in human and mouse
cornea tissue. The PPIP5K2-related phosphoinositide-3-kinase (PI-3 kinase) pathway, when inhibited, affects
AKT phosphorylation and keratocyte survival, leading to the apoptosis of corneal stromal keratocytes in KC
patients. We hypothesize that PPIP5K2 mutations alter TGFβ/AKT pathways, leading to degeneration of
corneal epithelial and stromal cells with subsequent thinning/bulging of the affected cornea. We will determine
how the identified mutations affect the cellular function of PPIP5K2 in vitro using primary human epithelial and
stromal cells in Aim 1. We will determine the KC-related corneal phenotypes in Ppip5k2-knockout mice using
comprehensive approaches including optical coherence tomography, functional vision screening, and slit lamp
exams followed by morphological examinations in Aim 2. On the other hand, we will screen PPIP5K2
mutations in additional familial and sporadic patients using whole exome sequencing. PPIP5K2-negative
multiplex families will be further examined with whole exome sequencing to identify novel mutations in Aim 3.
Upon successful completion, we will have a validated animal model of KC and potential novel targets for future
research directed at KC diagnosis and clinical therapy.

## Key facts

- **NIH application ID:** 9920145
- **Project number:** 5R01EY023242-06
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Yutao Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $435,422
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920145

## Citation

> US National Institutes of Health, RePORTER application 9920145, Cellular and Molecular Genetics of Keratoconus (5R01EY023242-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9920145. Licensed CC0.

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