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

Abstract

RNA-binding proteins (RBPs) are essential for post-transcriptional regulation and processing of RNAs. Pathogenic missense variants in RBPs underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, inclusion body myopathy, distal myopathy, and Paget's disease of the bone. Here, we present ten independent families with a severe, progressive, early-onset muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD), caused by heterozygous frameshift variants in the prion-like domain of hnRNPA2B1. We found that in contrast with the previously reported missense variants, the frameshift hnRNPA2B1 variants do not promote, but rather decelerate the fibrillization of the protein. Importantly, the frameshift variants harbor altered nuclear-localization sequences and exhibit reduced affinity for the nuclear-import receptor, Karyopherin-β2, which promotes their cytoplasmic accumulation in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with hnRNPA2B1 to include a severe, early-onset disease reminiscent of OPMD, caused by a distinct class of frameshift variants that alter its nucleocytoplasmic transport dynamics.

Molecular determinants of Karyopherin-β2 chaperone and disaggregation activity

“…Similar mutations in the PY-NLS of hnRNPA1 and hnRNPA2 also cause degenerative disease (40,41,116,117). We suggest that Kapβ2 chaperone activity is achieved by making an extensive network of both strong and weak interactions with cargo, displacing cargo:cargo interactions in favor of Kapβ2:cargo interactions.…”

“…Thus, it may be that with further technological improvements to AAV-based approaches , H8-E or even FL Kapβ2 could be delivered exogenously to treat diseases where nucleocytoplasmic trafficking of PY-NLS cargo is impaired, including ALS/FTD, MSP, oculopharyngeal muscular dystrophy, hereditary motor neuropathy, and related disorders (39)(40)(41)(124)(125)(126)(127).…”

“…If H12-E can chaperone FUS as effectively as Kapβ2, then the PY-epitope would be dispensable for Kapβ2 to chaperone cargo. We do not expect this possibility given the importance of the PYepitope integrity for human health (16,23,41,47,77,78). Collectively, this set of Kapβ2 truncations will enable us to define structural and sequence characteristics of Kapβ2 that are critical for its chaperone activity.…”

“…Indeed, several of the cargo recognized by Kapβ2 are prominent RNA-binding proteins (RBPs) with prion-like domains (PrLDs), which are connected to neurodegenerative disease via both pathology and genetics, including FUS, hnRNPA1, hnRNPA2, TAF15, and EWSR1 (8,10,11,15,16,(29)(30)(31)(32)(33)(34). In particular, mutations in genes encoding RBPs with PrLDs can cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multisystem proteinopathy (MSP), oculopharyngeal muscular dystrophy, hereditary motor neuropathy, and related disorders (35)(36)(37)(38)(39)(40)(41). In postmortem brain tissue of ALS/FTD patients, nuclear RBPs with PrLDs have been found to be mislocalized and aggregated in the cytoplasm of degenerating neurons (37,38,(42)(43)(44)(45)(46)(47)(48).…”

Oculopharyngodistal myopathy: The recent discovery of an old disease

“…OPDM1 patients with predominant proximal weakness are clinically indistinguishable from OPMD. Both findings may indicate the necessity for CGG repeat expansion analysis in LRP12 in patients with genetically uncharacterized isolated distal myopathy or OPMD patients without PABPN1 repeat expansion or HNRNPA2B1 mutations 13,17,20 …”