Specific heterozygous frameshift variants in hnRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy


Pre-Clinical Research

Poster Number: 22


Payam Mohassel MD, Hong Joo Kim PhD, Sandra Donkervoort MS, CGC, J. Paul Taylor MD, PhD, Carsten Bönnemann MD


1. NINDS, NIH, 2. St Jude's Children Research Hospital, 3. NINDS, NIH, 4. St Jude's Children Research Hospital, 5. NINDS/NIH, Bethesda, MD

RNA-binding proteins (RBPs) play critical roles in post-transcriptional regulation of RNAs, including RNA splicing, polyadenylation, stabilization, localization and translation. Pathogenic missense variants in RBPs such as TDP-43, hnRNPA2B1, FUS, and TIA-1 cause a spectrum of disease with pleomorphic phenotypic manifestations including amyotrophic lateral sclerosis/motor neuron disease, frontotemporal dementia, inclusion body myopathy, distal myopathy, and Paget’s disease of the bone. Previously, a multisystem proteinopathy (MSP) phenotype manifesting as Paget’s disease of the bone, inclusion body myopathy, motor neuron degeneration, and frontotemporal dementia caused by a missense variant in hnRNPA2B1 [(NM_002137, p.(D290V)] has been reported. Here, we present and characterize nine independent families with a severe, progressive early-onset oculopharyngeal muscular dystrophy-like phenotype, distinct from MSP, caused by a novel class of specific heterozygous frameshift variants in the low complexity domain of hnRNPA2B1. We found that in contrast with the missense variants that cause MSP, the frameshift hnRNPA2B1 variants do not promote liquid-liquid phase separation and fibrilization of the protein; instead, they modify its nucleocytoplasmic distribution by altering its C-terminal nuclear localization signal (PY-NLS). Thus, we expand the clinical phenotypes associated with hnRNPA2B1 to include severe, early-onset OPMD, caused by a distinct class of frameshifting variants with specific consequences on its nucleocytoplasmic transport dynamics. *For a full list of co-authors, please see the poster.