# Understanding the Role of CLP1 in Mammalian mRNA Transcription and Cleavage

> **NIH NIH F31** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $46,036

## Abstract

PROJECT SUMMARY/ABSTRACT
 Pontocerebellar hypoplasia (PCH) is a collection of pediatric neurodegenerative diseases caused by
mutations in genes that regulate mRNA processing or function. PCH subtype 10 (PCH10) is caused by
homozygous p.R140H mutation in the RNA kinase CLP1, a member of the mRNA 3’-end processing
machinery. The function of CLP1 in mRNA 3’-end processing and the pathophysiological mechanism of CLP1
p.R140H in PCH10 remains unknown.
 Prior studies in PCH10 patient-derived fibroblasts and induced neurons suggest CLP1 function may be
critical in certain cell types but not others. Motor neuron disease is a penetrant phenotype of PCH10, indicating
motor neurons are particularly vulnerable to loss of CLP1 activity or function. I performed RNA sequencing of
CLP1 p.R140H and CLP1 knockout human motor neurons and identified distinct signatures of alternative
polyadenylation suggesting these mutants act through different pathophysiological mechanisms, potentially
due to the loss of kinase activity rather than protein expression. Furthermore, a mouse model homozygous for
CLP1 p.K127A, a kinase-deficient variant, exhibits severe and progressive spinal motor neuron degeneration,
but a thorough characterization of mRNA processing in motor neurons with this variant has not been
performed. Since degeneration is a consistent phenotype of motor neurons with CLP1 p.R140H and p.K127A
mutation, and I identified mRNA processing defects in human motor neurons with the p.R140H mutation, I
predict perturbation of CLP1 kinase activity in stem cell-derived human motor neurons will alter mRNA 3’-end
processing. Based on these findings, I hypothesize that the loss of CLP1 kinase activity will affect the
recruitment of CLP1 to transcribed genes and alter mRNA 3’-end processing in human motor neurons. To test
this hypothesis, I will use CUT&RUN and mRNA 3’-end sequencing techniques to address the following
questions:
 1) How do variants affect the recruitment and distribution of CLP1 on transcribed genes in stem cell
 derived human motor neurons?
 2) Does CLP1 p.K127A alter mRNA processing in stem cell derived human motor neurons?

## Key facts

- **NIH application ID:** 10228844
- **Project number:** 1F31NS122207-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Geneva LaForce
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10228844

## Citation

> US National Institutes of Health, RePORTER application 10228844, Understanding the Role of CLP1 in Mammalian mRNA Transcription and Cleavage (1F31NS122207-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10228844. Licensed CC0.

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