# Analysis of pathogenic mosaic mutations in human Amyotrophic Lateral Sclerosis nervous system

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $460,625

## Abstract

Summary
 Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss
of motor neurons in the spinal cord and brain. While autosomal dominant mutations in several known genes can
cause familial ALS, most ALS cases (90-95%) display no family history so are classified as sporadic.
Mechanisms driving sporadic ALS are poorly understood, hindering the search for treatments and a cure.
Somatic mutations are DNA variants that arise after fertilization and are thus mosaic in the body, and somatic
mutations have been shown to be causal in several non-inherited neurological disorders. Our proposal aims to
test whether somatic mutations, in ALS risk genes or other genes, in the spinal cord or brain can cause sporadic
ALS. To test this hypothesis, we will use an interdisciplinary approach, combining the expertise in the clinical
features and genetics of ALS from the laboratory of Robert Brown DPhil., M.D. with expertise in somatic
mutations and single-cell analysis in the lab of Michael Lodato, Ph.D. We will analyze somatic mutations in a
consortium-generated whole-genome sequencing (WGS) dataset, and analyze somatic mutations in ultra-deep
(500x) whole-exome sequencing (WES) data generated in this proposal. These experiments will allow us to
study somatic mutations impacting sporadic ALS at all embryonic stages, including early somatic mutations
distributed across the body, and late embryonic somatic mutations that might occur in a committed central
nervous system progenitor and be restricted to the brain and spinal cord. Our preliminary data suggest that all
donors are marked by somatic mutations, some of which generate predicted deleterious changes. If successful,
we will open a new frontier in ALS genetics, and define new patient cohorts who are candidates for recently
developed, mutation-specific personalized therapeutics.

## Key facts

- **NIH application ID:** 10576017
- **Project number:** 1R21NS130539-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Michael Anthony Lodato
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $460,625
- **Award type:** 1
- **Project period:** 2022-09-10 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10576017

## Citation

> US National Institutes of Health, RePORTER application 10576017, Analysis of pathogenic mosaic mutations in human Amyotrophic Lateral Sclerosis nervous system (1R21NS130539-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10576017. Licensed CC0.

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