What is BPTAS?
Brachyphalangy, polydactyl and tibial aplasia/hypoplasia syndrome or BPTAS is an extremely rare disorder that manifests from an autosomal dominant inherited allele. Clinically, BPTAS is characterized by severe limb malformations, abnormalities of the pelvic bones, vertebrae, and other abnormalities such as sacral dimples and facial dysmorphia. Some patients report additional abnormalities such as congenital heart defects, and horseshoe kidneys. Although rare, the mechanisms and molecular etiology of BPTAS as well as the cause of heterogeneity in symptoms among patients is not clear.
In a recent publication in Nature, Mensah et al. (2023) show that BPTAS results from pathogenic biomolecular condensate formation which causes nucleoli arrest, cellular stress and cytotoxicity.
What are Biomolecular Condensates?
Eukaryotic cells are organized into distinct membrane-bound organelles that carry out specific functions and provide spatiotemporal control over cellular components, metabolic processes, and signaling pathways. However, recent literature shows that cells also contain membraneless organelles, composed of proteins and nucleic acids, that carry a wide array of cellular functions. These membraneless organelles, known as biomolecular condensates, can exist as liquids, solids or gels with a defined structure. The material state of biomolecular condensates and phase transitions are determined by the protein and/ or nucleic acid composition and intermolecular interaction networks.
A defining feature of biomolecular condensates is that they are enriched in proteins with intrinsically disordered domains (IDRs). IDRs are unstructured domains with a biased and often repetitive amino acid content. Due to their unstructured nature, IDRs form a promiscuous or multivalent interaction network with other proteins and nucleic acids. This mode of “fuzzy” and “sticky” interaction networks mediated by IDRs facilitates phase transitions into biomolecular condensates.
Pathogenic Biomolecular Condensate Formation as a Potential Biomarker and Driver of BPTAS
Mensah et al. performed whole genome sequencing (WGS) and whole exome sequencing (WES) on five patients with BPTAS to gain a better understanding of the underlying genetic abnormalities. Variants were called from the WGS and WES data and filtered using VarFish to identify de novo small variants with a high propensity to disrupt protein function. Upon variant filtration, the authors were able to identify a frameshift mutation in the C-terminal IDR of HMGB1, which causes a substitution of glutamic acid to arginine.
The HMGB1 gene encodes a low specificity DNA binding protein that is involved in various cellular processes, such as signaling, motility and chromatin looping. The authors found that substitution of acidic (glutamic acid) to basic amino acid (arginine) in the IDR enhanced the ability of HMGB1 to form and partition condensates. The mutant HMGB1 was found to incorporate into nucleoli, which are phase-separated multiphasic condensates, and disrupt their function.
To identify other genetic diseases involving potentially pathogenic condensates, the authors queried the open reading frames of over 5000 genes for C-terminal IDRs via metapredict, and then searched for frameshift variants in the dbSNP, ClinVar and COSMIC databases that cause replacement of amino acids with an arginine-rich basic tail. From this analysis, a list of 624 frameshift variants were identified in the C-terminal IDRs of proteins predicted to cause arginine rich substitutions. Interestingly, over 100 of these frameshift variants are classified as pathogenic in the ClinVar database.
Overall, this study suggests that disruption of condensates or the formation of pathogenic condensates may be a common feature of many genetic diseases. This provides opportunity for novel therapeutic regimens that alter biomolecular condensate biology as a modality for the treatment of genetic diseases.
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Haider M. Hassan, Data Scientist, Bridge Informatics
Haider is one of our premier data scientists. He provides bioinformatic services to clients, including high throughput sequencing, data pre-processing, analysis, and custom pipeline development. Drawing on his rich experience with a variety of high-throughput sequencing technologies, Haider analyzes transcriptional (spatial and single-cell), epigenetic, and genetic landscapes.
Before joining Bridge informatics, Haider was a Postdoctoral Associate at the London Regional Cancer Centre in Ontario, Canada. During his postdoc, he investigated the epigenetics of late-onset liver cancer using murine and human models. Haider holds a Ph.D. in biochemistry from Western University, where he studied the molecular mechanisms behind oncogenesis. Haider still lives in Ontario and enjoys spending his spare time visiting local parks. If you’re interested in reaching out, please email jennifer.martinez@old.bridgeinformatics.com or dan.ryder@old.bridgeinformatics.com
