# Gene Interaction in Development and Disease

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $434,429

## Abstract

ABSTRACT
Identification of genes responsible for genetic disease, analysis of their pathogenic mechanisms, and
development of compensatory interventions constitute major goals of human genetics research. Identification of
modifier genes and gene interaction can identify additional targets for intervention beyond the causal gene.
Genetic or pharmacological targeting of modifiers may provide more effective avenues for treatment. We have
focused on disorders with impaired function of ion channels and transporters that are localized in the membrane
of the lysosome. Regulation of lysosomal ion transport is important to maintenance of acidic pH and osmolarity
of the lysosome, as well as cytoplasmic ion concentration. During the current period, we evaluated modifiers of
the phosphatase FIG4 that functions in biosynthesis of the signaling lipid PI(3,5)P2. Through genome-wide
screens we identified the lysosomal co-transporter SLC12A9 as a modifier of FIG4 and the cause of a novel
lysosomal disorder with neurological and skeletal defects. The PI(3,5)P2 regulated ion transporters are
'druggable targets' for development of therapy for PI(3,5)P2 deficiency disorders. We found that CLCN7 and
PIP4K2C can compensate for FIG4 deficiency, based on their molecular functions. During the requested
termination year, we will further define the pathogenic mechanisms of SLC12A9 transporter defects and
interventions for the human disorder, and evaluate overexpression of PIKFYVE in Fig4 null mice using Crispr-a
as potential genetic therapy for PI(3,5)P2 deficiency disorders. We will functionally characterize a recurrent FIG4
mutation in two patients with ALS. We will also distribute the mutant mouse lines that have been generated and
publish the final papers from this long-running project. Together these aims extend our continuing studies of
lysosome function and neurological disease.

## Key facts

- **NIH application ID:** 11081950
- **Project number:** 3R01GM024872-46S2
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MIRIAM H MEISLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $434,429
- **Award type:** 3
- **Project period:** 1997-06-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11081950

## Citation

> US National Institutes of Health, RePORTER application 11081950, Gene Interaction in Development and Disease (3R01GM024872-46S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11081950. Licensed CC0.

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