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Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS.

Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP - Nature (2013)

Bottom Line: Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP.Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology.Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38120, USA.

ABSTRACT
Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.

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Identification of novel disease mutations in MSP and ALSa. Family 1 pedigree indicating individuals affected by dementia, myopathy, PDB, and ALS. The causative mutation was p.D290V/302V in hnRNPA2B1. b. Family 2 pedigree indicating individuals affected by myopathy and PDB. The causative mutation was p.D262/314V in hnRNPA1. c. The pedigree of a family with ALS. The causative mutation was p.D262/314N in hnRNPA1. d–e. Sequence alignment of hnRNPA2/B1 (d) and hnRNPA1 (e) orthologs showing evolutionary conservation of the mutated aspartate and surrounding residues. f. Sequence alignment of 4 human paralogs of the hnRNP A/B family in which the disease-affected residue and surrounding residues are highly conserved.
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Figure 1: Identification of novel disease mutations in MSP and ALSa. Family 1 pedigree indicating individuals affected by dementia, myopathy, PDB, and ALS. The causative mutation was p.D290V/302V in hnRNPA2B1. b. Family 2 pedigree indicating individuals affected by myopathy and PDB. The causative mutation was p.D262/314V in hnRNPA1. c. The pedigree of a family with ALS. The causative mutation was p.D262/314N in hnRNPA1. d–e. Sequence alignment of hnRNPA2/B1 (d) and hnRNPA1 (e) orthologs showing evolutionary conservation of the mutated aspartate and surrounding residues. f. Sequence alignment of 4 human paralogs of the hnRNP A/B family in which the disease-affected residue and surrounding residues are highly conserved.

Mentions: We identified a family (family 1) with dominantly inherited degeneration affecting muscle, bone, brain, and motor neurons that was clinically indistinguishable from prior families we have seen with VCP-related MSP (Fig. 1a and Supplementary Fig. 1 and Table 1). Sequencing the entire VCP gene including introns and exons in affected patients revealed no synonymous or non-synonymous variants. Genetic analysis of this family by exome sequencing and linkage analysis in parallel (Supplementary Fig. 1) identified a single novel variant (c.869/905A>T, p.D290V/302V) that co-segregated with disease and impacted the gene encoding hnRNPA2B1, a ubiquitously expressed RNA-binding protein (Fig. 1a). hnRNPA2B1 is expressed as two alternatively spliced isoforms: A2 and B1. The shorter hnRNPA2, which lacks 12 amino acids in the N-terminal region, is the major isoform accounting for ~90% of the protein in most tissues. This mutation substitutes valine for an aspartate residue that is evolutionarily conserved (Fig. 1d) and also centered in a motif that is conserved in multiple human paralogs in the hnRNP A/B family (Fig 1f and Supplementary Fig. 3).


Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS.

Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP - Nature (2013)

Identification of novel disease mutations in MSP and ALSa. Family 1 pedigree indicating individuals affected by dementia, myopathy, PDB, and ALS. The causative mutation was p.D290V/302V in hnRNPA2B1. b. Family 2 pedigree indicating individuals affected by myopathy and PDB. The causative mutation was p.D262/314V in hnRNPA1. c. The pedigree of a family with ALS. The causative mutation was p.D262/314N in hnRNPA1. d–e. Sequence alignment of hnRNPA2/B1 (d) and hnRNPA1 (e) orthologs showing evolutionary conservation of the mutated aspartate and surrounding residues. f. Sequence alignment of 4 human paralogs of the hnRNP A/B family in which the disease-affected residue and surrounding residues are highly conserved.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3756911&req=5

Figure 1: Identification of novel disease mutations in MSP and ALSa. Family 1 pedigree indicating individuals affected by dementia, myopathy, PDB, and ALS. The causative mutation was p.D290V/302V in hnRNPA2B1. b. Family 2 pedigree indicating individuals affected by myopathy and PDB. The causative mutation was p.D262/314V in hnRNPA1. c. The pedigree of a family with ALS. The causative mutation was p.D262/314N in hnRNPA1. d–e. Sequence alignment of hnRNPA2/B1 (d) and hnRNPA1 (e) orthologs showing evolutionary conservation of the mutated aspartate and surrounding residues. f. Sequence alignment of 4 human paralogs of the hnRNP A/B family in which the disease-affected residue and surrounding residues are highly conserved.
Mentions: We identified a family (family 1) with dominantly inherited degeneration affecting muscle, bone, brain, and motor neurons that was clinically indistinguishable from prior families we have seen with VCP-related MSP (Fig. 1a and Supplementary Fig. 1 and Table 1). Sequencing the entire VCP gene including introns and exons in affected patients revealed no synonymous or non-synonymous variants. Genetic analysis of this family by exome sequencing and linkage analysis in parallel (Supplementary Fig. 1) identified a single novel variant (c.869/905A>T, p.D290V/302V) that co-segregated with disease and impacted the gene encoding hnRNPA2B1, a ubiquitously expressed RNA-binding protein (Fig. 1a). hnRNPA2B1 is expressed as two alternatively spliced isoforms: A2 and B1. The shorter hnRNPA2, which lacks 12 amino acids in the N-terminal region, is the major isoform accounting for ~90% of the protein in most tissues. This mutation substitutes valine for an aspartate residue that is evolutionarily conserved (Fig. 1d) and also centered in a motif that is conserved in multiple human paralogs in the hnRNP A/B family (Fig 1f and Supplementary Fig. 3).

Bottom Line: Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP.Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology.Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38120, USA.

ABSTRACT
Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.

Show MeSH
Related in: MedlinePlus