Researchers Unravel Basis of Perlman Syndrome

Iranian researcher Mehdi Pirouz and his colleagues at Harvard Medical School in Boston have recently discovered that dysfunctional RNA molecules in cells are associated with Perlman syndrome and Wilms tumor.

Several years after identification of Perlman syndrome, a rare autosomal recessively inherited congenital overgrowth disease, its genetic and molecular etiology remained obscure. Recently, mutations in DIS3L2 gene were found to be responsible for the syndrome, characterized by overgrowth, facial dysmorphology, renal dysplasia, and multiple congenital abnormalities.

Perlman syndrome is associated with high neonatal mortality and a high risk of Wilms tumor in kidney. DIS3L2 is an enzyme responsible for RNA metabolism and degradation. However, the specific DIS3L2 targets as well as casual effects of DIS3L2 mutations remained to be discovered.

Using advanced genetic and molecular biology approaches as well as sequencing technologies, Dr. Mehdi Pirouz and his colleagues identified the targets of DIS3L2 enzyme in embryonic stem cells, Mehr News Agency reported.

Intriguingly, they discovered a previously unknown quality control pathway, in which DIS3L2 serves as a key molecular machine in living cells ensuring the degradation of mutated and therefore impaired RNA molecules. Accumulation of such dysfunctional RNA molecules in cells is associated with the overgrowth symptoms of Perlman syndrome and Wilms tumor.

“Cells in human body utilize various means to safeguard their precise gene expression programs, and any impairment of these pathways would induce genome instability and eventually cause different diseases,” Pirouz said.

“Our study introduces a novel quality control pathway that protects the living cells from detrimental consequences of RNA mutations. We aim to identify different aspects of DIS3L2 enzyme’s function that are linked to Perlman syndrome and Wilms tumor incidence. Eventually these studies will help us to understand the molecular basis of these diseases that can be targeted for therapy”.

The results of this study have been published in Cell Reports Journal.