Loss of Function Mutations in GEMIN5 Causes Neurodevelopmental Disorder

GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes.

Perturbing the physiological functions of RNA-binding proteins (RBPs) can lead to motor neuron diseases such as amyotrophic lateral sclerosis, and spinal muscular atrophy (SMA) among others. RBPs are critical for regulating multiple molecular functions including splicing, localization, translation, and mRNA stability.


An international group of collaborators led by Pediatricians at the Children's Hospital of Pittsburgh (Pittsburgh, PA, USA) contacted pediatricians, geneticists and neurologists from all over the globe, eventually collecting data from 30 patient families in 12 different countries. The team used genomic DNA from the proband as well as parents and siblings, when available, the exonic regions and flanking splice junctions of the genome were captured using the SureSelect Human All Exon V4 (50 Mb), the Clinical Research Exome kit (Agilent Technologies, Santa Clara, CA, USA) or the IDT x Gen Exome Research Panel v1.0 (Integrated DNA Technologies, Inc, Coralville, Iowa, USA). Massively parallel sequencing was done on a HiSeq2000 system (Illumina, San Diego, CA, USA) with 100 bp or greater paired end reads.

The scientists identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient induced pluripotent stem cell lines (iPSC)-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons.

Deepa S. Rajan, MD, an assistant professor of pediatrics and a senior author of the study, said, “Children came into the clinic with non-specific symptoms, such as developmental delay and abnormal gait. Their doctors ran all the possible tests, including assessing a child's metabolic function, to no avail--their conditions had no easy explanation. It was not until we did an extensive genome analysis that we found that these patients had mutations in the GEMIN5 gene.”

The authors concluded that their findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome. Also that biallelic variants in GEMIN5 cause developmental delay, motor dysfunction, and cerebellar atrophy and reduce snRNP complex assembly proteins, impair snRNP assembly and misregulate RNA targets. The study was published on May 7, 2021 in the journal Nature Communications.

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