A Novel Multisystem Proteinopathy Caused by a Missense ANXA11 Variant

Abstract

Objective:Protein misfolding plays a central role not only in amyotrophic lateral sclerosis (ALS), but also in other conditions, such as frontotemporal dementia (FTD), inclusion body myopathy (hIBM) or Paget's disease of bone. The concept of multisystem proteinopathies (MSP) was created to account for those rare families that segregate at least 2 out of these 4 conditions in the same pedigree. The calcium-dependent phospholipid-binding protein annexin A11 was recently associated to ALS in European pedigrees. Herein, we describe in detail 3 Brazilian families presenting hIBM (isolated or in combination with ALS/FTD) caused by the novel p.D40Y change in the gene encoding annexin A11 (ANXA11). Methods: We collected clinical, genetic, pathological and skeletal muscle imaging from 11 affected subjects. Neuroimaging was also obtained from 8 patients and 8 matched controls. Results: Clinico-radiological phenotype of this novel hIBM reveals a slowly progressive predominant limb-girdle syndrome, but with frequent axial (ptosis/dropped head) and distal (medial gastrocnemius) involvement as well. Muscle pathology identified numerous rimmed vacuoles with positive annexin A11, TDP-43 and p62 inclusions, but no inflammation. Central nervous system was also involved: two patients had FTD, but diffusion tensor imaging uncovered multiple areas of cerebral white matter damage in the whole group (including the corticospinal tracts and frontal subcortical regions). Interpretation: These findings expand the phenotypic spectrum related to ANXA11. This gene should be considered the cause of a novel multisystem proteinopathy (MSP type 6), rather than just ALS.

Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis

“…MSP has also been linked to mutations in other ALS-associated genes, namely HNRNPA1 and HNRNPA2B1 ( Kim et al, 2013 ), SQSTM1 ( Bucelli et al, 2015 ), and a novel missense variant of Annexin A11 ( ANXA11 ) ( Leoni et al, 2021 ). ANXA11 mutations have been linked to ALS in three European families ( Smith et al, 2017 ) and to FTD in one Chinese family ( Zhang et al, 2018 ).…”

“…Like ALS, IBM features protein misfolding, with proteins previously identified in pathological inclusions generally classed as structural proteins, RBPs, or regulators of protein quality control pathways. As a vesicular trafficking protein, ANXA11 does not fall into any of these categories, however Leoni et al (2021) identify ANXA11 pathology this indicates that a more widespread characterization of MSP is needed. ANXA11 mutations are associated with cognitive and behavioral changes which correlate with white matter abnormalities, although not with cortical atrophy.…”

Common pathophysiology for ANXA11 disorders caused by aspartate 40 variants

“…Mutations in genes encoding other proteins with intrinsically disordered domains (IDD) and functionally involved in SGs biology have been reported to cause myopathies. Specifically, mutations in VCP , 12 HNRNPA2B1 and HNRNPA1 , 13 SQSTM1 , 14 MATR3 , 15 and the aforementioned ANXA11 10 lead to adult‐onset myopathies with an accumulation of cytoplasmic aggregates in the muscle. In pediatric patients, however, only HNRNPA2B1 is known to cause a childhood‐onset myopathy, 16 resulting in a phenotype reminiscent of oculopharyngeal muscular dystrophy but with an exceedingly early onset.…”

Development of a standard of care for patients with valosin-containing protein associated multisystem proteinopathy

“…The previously used term, inclusion body myopathy associated with Paget’s disease of bone (and frontotemporal dementia (IBMPFD), is no longer favored given the other phenotypes that may occur. Other genes that are associated with a similarly presenting MSP syndrome include heterogeneous nuclear ribonucleoprotein A2B1 and A1 ( hnRNPA2B1, hnRNPA1 ), sequestosome 1 ( SQSTM1 ), matrin 3 ( MATR3 ), T-cell restricted intracellular antigen 1 ( TIA1 ), optineurin ( OPTN ), annexin 11 ( ANXA11 ), and profilin 1 ( PFN1I ), many of which share common pathophysiology of disruption of RNA stress granule function or autophagic degradation, and patients presenting with these MSP syndromes may benefit from similar diagnostic and treatment strategies [ 1 , 2 ].…”

“…OPTN mutations are another cause of familial ALS and ALS-FTD [ 14 ], and genetic variation in OPTN is a risk factor for development of PDB [ 14 , 15 ]. Most recently, mutations in ANXA11 have been associated with IBM with ALS/FTD and have been proposed to be categorized as MSP6 [ 2 ]. Missense mutations in PFN1 are associated with familial ALS whereas PFN1 haploinsufficiency is associated with early onset and polyostotic PDB [ 16 , 17 ].…”