Altay, M.F., Gregor, A., Braun, D., Rieubland, C., Gautschi, M., Perret Hoigné, E., Schiller, R., Keren, B., Afenjar, A., Undiagnosed Diseases Network, , Martinez-Agosto, J.A., Rosenfeld, J.A., Zweier, C. (2026). Heterozygous loss of SRRM1 may be associated with neurodevelopmental phenotypes and anomalies in cell growth and neurite morphology.  Europ. J. Human Genet. 34(2): 201--208.

FBrf0264466

Research paper

Serine/arginine repetitive matrix protein 1 (SRRM1) is a key component of spliceosomes and plays various roles in messenger RNA processing. To date, its function in the nervous system has not been elucidated, and germline variants in SRRM1 have not yet been implicated in disease. Through international collaboration, we have identified three individuals harbouring heterozygous truncating variants in SRRM1, presenting variably with developmental delay, intellectual disability, short stature, behavioural and skeletal anomalies, and facial dysmorphism. Two of the variants occurred de novo, while the third could not be tested in the parents. Reduction of SRRM1 to 50% in SKNBE2 cells by introducing a truncating variant via CRISPR-Cas9 editing, followed by differentiation into neuron-like cells, resulted in impaired cell proliferation, migration, and neurite outgrowth compared to wild-type cells. Additionally, the role of SRRM1 in nervous system development and functioning was investigated in vivo using a Drosophila model. Pan-neuronal knockdown of the orthologue Srrm1 led to reduced viability, while motoneuronal knockdown impaired gross neurological function. Taken together, we provide multiple lines of evidence that loss of SRRM1 is associated with nervous system-related phenotypes, and that its haploinsufficiency may be causative for a neurodevelopmental disorder.

PMC12858978 (PMC) (EuropePMC)