Splicing and frameshift variants in QSER1 may be involved in developmental phenotypes. HGG Adv 2026 Jan 15;7(1):100539
Date
10/27/2025Pubmed ID
41139957Pubmed Central ID
PMC12648955DOI
10.1016/j.xhgg.2025.100539Scopus ID
2-s2.0-105021122737 (requires institutional sign-in at Scopus site)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.
Author List
Fischer MC, Reis LM, Lenberg J, Friedman J, Seese SE, Muheisen S, Writzl K, Golob B, Peterlin B, Semina EVAuthor
Elena V. Semina PhD Chief, Professor in the Ophthalmology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsChild
Child, Preschool
Developmental Disabilities
Female
Frameshift Mutation
Humans
Male
Neurodevelopmental Disorders
Phenotype
RNA Splicing
Zebrafish
