PUBLICATION
Splicing and frameshift variants in QSER1 may be involved in developmental phenotypes
- Authors
- Fischer, M.C., Reis, L.M., Lenberg, J., Friedman, J., Seese, S.E., Muheisen, S., Writzl, K., Golob, B., Peterlin, B., Semina, E.V.
- ID
- ZDB-PUB-251028-3
- Date
- 2025
- Source
- HGG advances : 100539100539 (Other)
- Registered Authors
- Keywords
- Axenfeld-Rieger syndrome, PRR12, QSER1, loss-of-function, neurodevelopmental disorder
- MeSH Terms
-
- Animals
- Child
- Child, Preschool
- Developmental Disabilities/genetics
- Female
- Frameshift Mutation*
- Humans
- Male
- Neurodevelopmental Disorders/genetics
- Phenotype
- RNA Splicing*
- Zebrafish/genetics
- PubMed
- 41139957 Full text @ HGG Adv
Citation
Fischer, M.C., Reis, L.M., Lenberg, J., Friedman, J., Seese, S.E., Muheisen, S., Writzl, K., Golob, B., Peterlin, B., Semina, E.V. (2025) Splicing and frameshift variants in QSER1 may be involved in developmental phenotypes. HGG advances. :100539100539.
Abstract
Human development is a complex process that requires precise control of gene expression through regulatory proteins. Recently, heterozygous variants in PRR12, encoding a proline-rich regulatory protein, were found to cause a variable phenotype involving developmental delay/cognitive impairment, neuropsychiatric diagnoses, structural eye anomalies, congenital heart and kidney defects, and poor growth. QSER1, encoding glutamine- and serine-rich protein 1, represents a paralog of PRR12 that shares 28% overall identity at the protein level and stronger conservation (43%) in the C-terminal region. QSER1 deficiency in human embryonic stem cells causes hypermethylation of many key transcription factor genes, implicating it in the development of multiple organs. Here we present three unrelated individuals with neurodevelopmental phenotypes, variable other multisystem anomalies, and heterozygous variants in QSER1. This includes two novel de novo frameshift alleles (p.(Lys1565Argfs*36) and p.(Phe896fs*28)), and one ultra-rare canonical splice site variant resulting in a combination of abnormal transcripts, frameshift (p.(Glu1393Glyfs*26)) and in-frame deletion of a conserved amino acid (p.(Glu1393del)), supported by in silico predictions and minigene assays. In situ hybridization revealed dynamic and broad expression of qser1 in zebrafish embryos, including a strong presence in the developing brain. These data suggest a possible role for QSER1/qser1 in vertebrate development and human disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping