Hong Joo Kim, a postdoctoral fellow at St. Jude Children’s Research Hospital in Memphis, Tenn., was awarded an MDA development grant totaling $180,000 over a period of three years to study new genes for a newly recognized disorder called multisystem proteinopathy (MSP).
MSP causes symptoms that are seen frontotemporal dementia (FTD) and Paget’s disease of bone (PDB), and in two diseases covered by MDA — amyotrophic lateral sclerosis (ALS) and inclusion-body myositis (IBM). “Patients with this rare, inherited multisystem disease may experience isolated IBM, FTD, ALS or PDB, which can be indistinguishable from other familial and sporadic cases of these disorders, or the disease may manifest in multiple tissues in the same patient,” Kim says.
While a gene has been discovered that causes MSP, this gene is not responsible for the disease in other families. That led Kim and colleagues to use modern gene-hunting techniques to search for other potential candidates.
They found two such genes, called heterogeneous nuclear ribonucleoproteins (hnRNPA2B1 andhnRNPA1), which bind to a cellular messenger called RNA. Alterations in binding and transport are increasingly seen as likely causes of multiple diseases in the nervous system. “Studying the genes that cause this rare multisystem syndrome represents a unique opportunity to identify a fundamental molecular defect that underlies multiple common age-related diseases,” Kim says.
The disease-causing mutations they have found appear to increase the likelihood that individual units of protein will clump together, a feature of many other neurodegenerative diseases. Kim plans to generate fly and mouse research models that contain either the normal or mutant forms of hnRNPA2B1 and A1, in order to study their effects. “We seek to recapitulate the full spectrum of MSP, to elucidate the molecular mechanism of pathogenesis, and to identify target genes that are misregulated in hnRNPA2B1- and A1-associated diseases,” she says, which may lead to new strategies for treating MSP and other diseases.
Funding for this MDA grant began Feb. 1, 2013.