Beta thalassaemia, a prevalent inherited haemoglobin disorder, poses significant challenges worldwide, particularly in Southern Mediterranean countries where the incidence rate at birth is 36.8 cases per 100,000 newborns. This condition arises from mutations in the human globin genes, resulting in impaired production of haemoglobin and consequently anaemia. In Malta, approximately 40 individuals suffer from beta thalassemia major and are dependant on lifelong blood transfusions every 4-6 weeks for survival. Despite medical advances, management of such patients remains complex, with complications including iron overload and risk of transfusion-transmitted infections. Moreover, curative options such as bone marrow and haematopoietic stem cell transplantation remain limited to a small subset of patients, underscoring the urgent need for innovative and sustainable approaches in treatment and care.
Clinical investigations and molecular findings have demonstrated that elevated levels of foetal haemoglobin (HbF) in patients with haemoglobinopathies help in decreasing the severity of associated clinical symptoms. Novel therapeutic approaches are hence aiming to understand the molecular mechanisms driving increased HbF levels. Of particular interest for investigation in this context is the benign genetic disorder known as hereditary persistence of foetal haemoglobin (HPFH). This condition is characterised by the sustained production of elevated HbF levels (>1%) throughout adulthood, resulting from disrupted globin gene switching. Notably, in Malta, five families are known to be affected by HPFH due to a truncation mutation in the KLF1 gene. This provides a unique opportunity to understand the molecular defects that cause HPFH and its potential implications for management of beta thalassaemic patients.
My master’s research, conducted under the supervision of Prof. Joseph Borg, focused on unravelling these intricate pathways by studying three Maltese families affected by HPFH. Through comprehensive analysis, a total of 205 unique mutations were identified across all HPFH-affected individuals. Of particular interest were novel mutations within the NLRP3 and RPS9 genes, which emerged as potential regulators of elevated HbF levels. Furthermore, 53 proteins exhibiting significant correlation with HbF levels in HPFH-affected subjects were identified through proteomic analysis, suggesting their potential involvement in the regulation of globin genes. These findings not only deepen our understanding of HPFH, but also pave the way for the development of targeted therapeutic interventions aimed at improving the lives of patients affected with haemoglobin disorders.
The work carried out in this master’s dissertation is available and was funded by the Tertiary Education Scholarships Scheme, financed by the Ministry for Education and Employment in Malta.
Nikita Camilleri completed a Master of Science degree in Applied Biomedical Science at the Faculty of Health Sciences, University of Malta, and is currently a medical lab scientist at Mater Dei Hospital.
