Molecular Pathology

NON-COMMUNICABLE DISEASES / Neurobiology

Research Interests

RNA-protein interactions. Defective RNA processing and neurodegeneration. Genetic disease caused by defective splicing.

Description of Research

The field of molecular diagnostics is critical for accurately classifying genetic alterations, particularly those variants of uncertain significance (VUSs), which are notoriously challenging to interpret globally. This work is vital in populations facing unique demographic and healthcare challenges, such as those in the Middle East and North Africa (MENA). Recent studies from our lab have demonstrated the necessity of functional molecular research, especially in regions characterised by high rates of consanguinity or limited access to advanced genetic screening.

Research conducted in Türkiyefocuses on characterising splicing variants associated with Rare Neurodevelopmental Disorders (RNDDs) in pediatric patients from consanguineous Turkish families. RNDDs are known to represent a significant portion of all rare diseases, and variants that alter pre-mRNA splicing constitute a large segment of pathogenic variants.. The significance of this research for the Turkish population, and by extension, other high-consanguinity populations, is substantial. Türkiye has a high rate of consanguineous marriage (24%), thus specific founder effects or recurrent homozygous variants are more likely to occur. The study explored the therapeutic potential of using engineered U1 small nuclear RNAs developed in ICGEB Trieste to correct these splicing defects. These provided a partial rescue of the mis-splicing phenotype for 4 of the variants in lab models; suggesting that such therapeutic strategies hold promise for achieving beneficial consequences for patients with rare neurogenetic conditions. In populations with a high consanguinity rate, the accurate classification of these variants and the potential use of such therapeutic strategies can help improve patient management and reduce the considerable economic burden associated with rare diseases.

A study focusing on breast cancer genetics examined the effects of three novel Variants of Uncertain Significance (BRCA1 exon 11 variants) identified in Libyanbreastcancerpatients. Breast cancer is a major health challenge in Africa, ranking as the second most common cancer among women over the age of 50. Our research addresses a critical diagnostic gap in North Africa where comprehensive screening initiatives are urgently needed because the specific impact and prevalence of BRCA1 mutations in Africa are still very poorly understood and challenges in organising preventive screenings and accessing medical care often lead to delayed diagnoses and high mortality rates. Using computational analysis followed by minigene assays in human breast cancer cell lines, researchers confirmed that the c.2363T>G variant significantlyaltered the splicing pattern of BRCA1 exon 11, causing a decrease in the full-length isoform and an increase in aberrant isoforms. This finding is critical because the reduction of full-length BRCA1 protein, combined with the resultant amino acid change (V788G) that falls within a domain critical for interaction with the DNA repair factor RAD51, strongly suggests potential pathogenicity.

This work contributes to the essential effort of dissecting the functional impact of BRCA1 VUSs to inform cancer risk and prevention strategies. For low- and middle-income countries, where genetic counseling, screening, and risk-reducing surgery needs are often unmet, research that accurately characterises the pathogenicity of local variants is an indispensable step toward improving clinical management for patients with hereditary cancer risk.

In addition, our laboratory focuses on TAR DNA-binding protein 43 (TDP-43), a crucial RNA-binding protein (RBP) that is ubiquitously expressed and vital for multiple levels of RNA processing, including splicing, transcription, transport, and translation. TDP-43 dysfunction is central to various neurodegenerative and muscular diseases. In Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), TDP-43 forms aberrant cytoplasmic inclusions in motor neurons. Aggregates are also found in skeletal muscles of patients with Inclusion Body Myositis (IBM) and other myopathies. Recent research has aimed to unravel the complex mechanisms of TDP-43 dysfunction and suggests that the cellular environment significantly influences TDP-43’s function and cell-type-specific splicing. Crucially, splicing alterations of TDP-43-dependent transcripts were confirmed in patient tissues, including IBM muscle and brain regions from ALS and FTLD patients. A final research area explores the molecular connection between TDP-43 and Niemann Pick type C (NPC) disease, a metabolic disorder characterised by severe neurodegeneration.

Recent Publications