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. 2022 Apr 18;15(1):89.
doi: 10.1186/s12920-022-01237-5.

Intellectual disability associated with craniofacial dysmorphism due to POLR3B mutation and defect in spliceosomal machinery

Mostafa Saghi  1 , Kolsoum InanlooRahatloo  2 , Afagh Alavi  1 , Kimia Kahrizi  1 , Hossein Najmabadi  1
Affiliations

Intellectual disability associated with craniofacial dysmorphism due to POLR3B mutation and defect in spliceosomal machinery

Mostafa Saghi et al. BMC Med Genomics. .

Abstract

Background: Intellectual disability (ID) is a clinically important disease and a most prevalent neurodevelopmental disorder. The etiology and pathogenesis of ID are poorly recognized. Exome sequencing revealed a homozygous missense mutation in the POLR3B gene in a consanguineous family with three Intellectual disability with craniofacial anomalies patients. POLR3B gene encoding the second largest subunit of RNA polymerase III.

Methods: We performed RNA sequencing on blood samples to obtain insights into the biological pathways influenced by POLR3B mutation. We applied the results of our RNA-Seq analysis to several gene ontology programs such as ToppGene, Enrichr, KEGG.

Results: A significant decrease in expression of several spliceosomal RNAs, ribosomal proteins, and transcription factors was detected in the affected, compared to unaffected, family members.

Conclusions: We hypothesize that POLR3B mutation dysregulates the expression of some important transcription factors, ribosomal and spliceosomal genes, and impairments in protein synthesis and splicing mediated in part by transcription factors such as FOXC2 and GATA1 contribute to impaired neuronal function and concurrence of intellectual disability and craniofacial anomalies in our patients. Our study highlights the emerging role of the spliceosome and ribosomal proteins in intellectual disability.

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Conflict of interest statement

The authors have no conflict of interest.

Figures

Fig. 1
Fig. 1
Pedigree of a family with more than two affected persons due to a homozygous missense mutation in POLR3B. II-1 is proband. II-2, II-3, II-4, II-5, II-6 and three healthy cousins (sex and age-matched) involved in this study
Fig. 2
Fig. 2
Differentially expressed genes between POLR3B mutant patients and 6 controls. a The heat map showing DEGs between POLR3B mutant patients vs controls. b Comparison of POLR3B expression in POLR3B mutant patients and controls. c Comparison of POLR3B isoform expression in POLR3B mutant patients and controls
Fig. 3
Fig. 3
The top 10 down-regulated and up-regulated genes in POLR3B mutant patients vs controls
Fig. 4
Fig. 4
protein–protein interactions (PPI) of the DEGs. Nodes and edges represented by colored circles and arrows respectively. The big circle nodes are the hub proteins
Fig. 5
Fig. 5
Transcriptional regulators of DEGs and miRNA. Transcriptional regulators of DEGs. Diamonds represent TFs and red circles show nodes, they are related by arrows
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