Rapid progressive ALS in a patient with a DNAJC7 loss-of-function mutation

Abstract

Recently, DNAJC7 was found to be associated with amyotrophic lateral sclerosis (ALS) in a single large-scale exome sequencing study. 1 Multiple protein-truncating variants were detected in individuals with ALS that were absent in control subjects. 1 DNAJC7 encodes a member of the DnaJ heat-shock protein family (HspP40), which functions in protein homeostasis, including protein folding and degradation. 2 To validate the pathogenic role of DNAJC7 in ALS and further understand the relevant clinical features, we screened a Taiwanese ALS cohort for DNAJC7 mutations.

Hyperosmotic-stress-induced liquid-liquid phase separation of ALS-related proteins in the nucleus

“…Thus, we hypothesized that one of the reasons for the difference in disassemble ability of FUS and TDP-43 granules is that they contain different chaperone components, which may result in their distinct biophysical and material properties in the granules. Intriguingly, our study showed the importance of Hsp40 to chaperone the assembly and maintenance of FUS condensates (Gu et al, 2020), and the loss of function of Hsp40 was found to be related to ALS, such as the mutation of class III Hsp40-DnaJC7 that was found in patients with ALS (Farhan et al, 2020;Jih et al, 2020). Moreover, recent studies showed that Hsp70 family chaperones can maintain the liquidity of TDP-43 (Gu et al, 2021;Yu et al, 2021).…”

Mutations in Hsp90 Cochaperones Result in a Wide Variety of Human Disorders

“…Mutations in DNAJC7 have been linked to amyotrophic lateral sclerosis, a progressive nervous system disease that affects nerve cells in the brain and spinal cord. Most of observed mutations were protein-truncating variants, and in some cases protein loss was confirmed ( Farhan et al, 2019 ; Jih et al, 2020 ; He et al, 2021 ). However, one missense mutation that alters a residue in one of the TPR domains was found ( Wang et al, 2020a ).…”

Regulation of p53 and Cancer Signaling by Heat Shock Protein 40/J-Domain Protein Family Members

“…DNAJC7, also known as Tetratricopeptide Repeat 2 (TPR2), contains two TPR domains that bind to both HSP70 and HSP90, in addition to the J domain for stimulating ATP hydrolysis and polypeptide binding by HSP70 [173]. Accumulating studies suggest the involvement of DNAJC7/TPR2 in amyotrophic lateral sclerosis (ALS), likely through binding to natively folded tau and inhibiting tau aggregation [165,174,175]. DNAJC7/TPR2 binds to many other proteins, together with HSP70, including progesterone receptor, RAD9, a U-box E3 ubiquitin ligase UFD2a, and constitutive active androstane receptor (CAR)/Nuclear Receptor Subfamily 1 Group I Member 3 (NR1I3) [176][177][178][179].…”