PI: Florence Malisan
Co-investigators: Ivano Condò, Gian Paolo Ussia
HAX-1 is a potential biomarker for cardiomyopathies
Cardiomyopathies are a heterogeneous group of diseases affecting the myocardium, due to various causes but often genetically determined. Predicting any given patient’s course in terms of development of symptoms or lethal arrhythmias remains a challenge. Friedreich’s Ataxia (FRDA) is a hereditary disorder due to deficient expression of the mitochondrial protein frataxin characterized by progressive neurodegeneration and frequent cardiomyopathy since approximatively 60% of FRDA patients die from heart failure. Searching for genes involved in FRDA pathogenesis, microarray analysis revealed that overexpression of frataxin correlates with overexpression of HS-1 associated protein X-1 (HAX-1) which comprises a family of proteins playing important roles in the regulation of apoptosis. Interestingly, HAX-1 plays a crucial role in cell survival in cardiac tissue.
We have shown that low levels of frataxin in FRDA cell lines and primary peripheral mononuclear cells (PBMCs) of FRDA patients correspond to reduced levels of HAX-1 (F. Malisan and F. Amati, manuscript in preparation) confirming the positive relashionship between frataxin and HAX-1 both at protein and mRNA level. This expression pattern is noteworthy in PBMCs of FRDA patients affected by cardiac disease, especially for mRNA expression.
We therefore sought to investigate the expression and role of HAX-1 in cardiomyopathy patients in order to evaluate HAX-1 as a molecular biomarker for cardiomyopathy. Moreover, we plan to study the physiological variations of circulating microRNAs to evaluate whether and which microRNAs are involved in any differences found in HAX-1 expression and to examine which of them may be important as biomarkers for cardiomyopathy.
Our results will contribute to the discovery of novel genetic “risk” or “protective” factors in cardiomyopathy that may also emerge as new therapeutic targets.
PI: Marco Barchi
Co-investigators: Paola Grimaldi, Pellegrino Rossi
Impact of genetic and epigenetic alterations on transmission of aneuploidies in mammals
Chromosome abnormalities occur with high frequency in humans. Of different classes of aberrations, aneuploidy is the most common and clinically relevant. Except few cases, monosomies and and trisomies of the autosomes are incompatible with normal development. However, the consequences are less severe for the sex chromosomes, so that X-chromosomes monosomy (45,X0), condition associated with Turner syndrome (TS), and trisomy (47,XXY) associated with Klinefelter syndrome (KS), are “enriched” among liveborns.
In mammals, proper homologous chromosomes pairing and segregation of the sex chromosomes and autosomes during meiosis, rely on homologous recombination, a process that is fired by the formation of double strand breaks (DSBs) by the SPO11 protein. DSBs landscape is not random, as they are constrained to specific regions of the genome, called “hot spots”, by the histone-lysine N-methyltransferase PRDM9.
In this project we will explore how genetic and epigenetic alterations in germ cells genome might impact on fertility and proper chromosome segregation in gametes. Using knock-in mouse models developed in our lab, we will investigate the specific function of single Spo11 splice isoforms in proper segregation of the X-Y chromosome and autosomes. Results obtained with mice will be tested on samples from human patients; i.e. KS-parents, KS, non-obstructive azoospermic (NOA) or oligospermic patients with an unbalanced chromosome number. In addition, we will study if variations in the expression levels of the epigenetic modifier PRDM9, induced pharmacologically by synthetic agonist of cannabinoid receptors, may affect crossover formation leading to aneuploidy. This information could be potentially relevant for Marijuana smokers. ,