Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy

Abstract

Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.

A minimal construct of nuclear-import receptor Karyopherin-β2 defines the regions critical for chaperone and disaggregation activity

“…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 PY-epitope integrity for human health ( 16 , 23 , 41 , 48 , 79 , 80 ). 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 , 42 ). In the postmortem brain tissue of ALS/FTD patients, specific nuclear RBPs with PrLDs have been found to be depleted from the nucleus and mislocalized and aggregated in the cytoplasm of degenerating neurons ( 37 , 38 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ).…”

“…Mutations that affect the PY-NLS or the biophysical properties of its cargo can also reduce Kapβ2 function ( 16 , 20 , 41 ). PY-NLS mutations can be particularly devastating and cause juvenile ALS, as with FUS P525L , where the conserved proline of the PY-NLS is mutated to leucine ( 79 , 80 ).…”

Oculopharyngodistal myopathy: The recent discovery of an old disease

“…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 Other important findings were that six of seven patients reported by Shimizu and colleagues developed neck muscle weakness and one patient presented with dropped head syndrome. Imaging findings showed prominent involvement of rectus abdominis and paraspinal muscles.…”

Estudo clínico, histológico e molecular de pacientes com miopatias distal e miofibrilar

“…Um paciente com fenótipo de fraqueza de cinturas e patologia miofibrilar, com presença de vacúolos marginados, apresentou uma variante de significado incerto, ainda não descrita, no gene HNRNPA2B1. Variantes missense em proteínas de ligação de RNA, incluindo HNRNPA2B1 estão sendo reconhecidas como causadoras de um espectro de fenótipos de doenças, incluindo esclerose lateral amiotrófica, demência frontotemporal, distrofia óculo-faringea e miopatia de corpos de inclusão hereditária (Kim et al, 2022). A variante que encontramos no paciente se encontra no resíduo 269 em um domínio semelhante ao príon (príon-like domain), que vai do 261 ao 303 e apresenta um risco de patologia com inclusões proteícas que se espalham no tecido (Kim et al, 2015).…”