A Study in Which the VHIR Has Participated Discovers a New Pediatric Disease

The Vall d'Hebron Research Institute (VHIR) has recently participated in an international study, coordinated by the Children's Hospital of Philadelphia, which has led to the discovery of a new pediatric neurodegenerative disease. The results of this work have been published in the prestigious scientific journal Science Advances under the title “Histone H3.3 beyond cancer: Germline in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients”.

The dysregulation of the modification of histones, which are proteins critical to the packaging of DNA in the cell nucleus, is associated with the appearance of cancer, in addition to other diseases such as neurological and psychological disorders and, even, cardiovascular diseases. Precisely, the large number of diseases that derive from histone dysregulation makes the understanding of their function vital to understand the pathophysiology of all these disorders and to develop treatments.

The results of this research work make possible the molecular characterization of a new pediatric disorder, which is caused by genetic variants in the H3-3A and H3-3B genes that encode for histone H3.3. This disease has a heterogeneous clinical phenotype. For example, 21% of patients have clear neurological degeneration, and 26% of the cohort show cortical atrophy, in some cases associated with untreatable epilepsy. Severity also has a considerable degree of variation, and is reflected, for example, in the age at which patients begin to walk, which can range from twenty-one months to more than four years, or the age at which they sit, which varies between eight months and four and a half years.

The VHIR research group in Clinical and Translational Bioinformatics, headed by Dr. Xavier de la Cruz, is the one who has led the computational analysis of these variants and has proposed the mechanism that explains their functional impact.

The study analysed a cohort of 46 patients carrying mutations in the histone family H3-3A and H3-3B not related to progressive neurological dysfunction and congenital anomalies without malignancies. “The results suggest that the mechanism of the variants studied is different from that of somatic mutations, although they may converge in the control of cell proliferation. The experimental studies have provided a solid vision of the relationship between the causal genetic variants and different aspects of the clinical phenotype”, explain Dr. de la Cruz and Dr. Natàlia Padilla, member of the research group. “Computational analysis has shown how the variants can affect the interactions of H3.3 with DNA, with other histones in the nucleosome, with regulating proteins of gene expression and with histone chaperones”.

The conclusions drawn from the study establish the existence of this disorder for the first time. For this reason, these researchers consider that this work “will help the molecular diagnosis of the disease. Furthermore, the knowledge of the possible molecular impact mechanisms of the variants can be an important source of information to find suitable drugs for this disorder”.


De la Cruz Montserrat, Fco. Xavier
Fitxa personal
Padilla Sirera, Natalia
Fitxa personal

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