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DNAJ/HSP40 HOMOLOG, SUBFAMILY B, MEMBER 2; DNAJB2

DNAJ/HSP40 HOMOLOG, SUBFAMILY B, MEMBER 2; DNAJB2

Alternative titles; symbolsHEAT-SHOCK PROTEIN, DNAJ-LIKE 1; HSJ1HEAT-SHOCK 40-KD PROTEIN 3; HSPF3HGNC Approved Gene Symbol: DNAJB2Cytogenetic location: 2q35 ...

Alternative titles; symbols

  • HEAT-SHOCK PROTEIN, DNAJ-LIKE 1; HSJ1
  • HEAT-SHOCK 40-KD PROTEIN 3; HSPF3

HGNC Approved Gene Symbol: DNAJB2

Cytogenetic location: 2q35 Genomic coordinates (GRCh38): 2:219,279,365-219,286,894 (from NCBI)

▼ Description
The DNAJB2 gene encodes a molecular cochaperone member of the heat shock protein family. These proteins play important cellular roles in correct protein folding, in the response to protein misfolding, and in the degradation of misfolded proteins (summary by Blumen et al., 2012).

▼ Cloning and Expression
The E. coli heat-shock protein DnaJ has been implicated in protein folding and protein complex dissociation. By screening a human frontal cortex cDNA expression library with antibody against paired helical filament proteins (see 157140), Cheetham et al. (1992) identified a novel gene, HSJ1, which shows sequence similarity to DnaJ. They isolated cDNAs corresponding to 2 alternatively spliced HSJ1 transcripts that differ by the presence or absence of a 1.1-kb insert. The cDNA lacking the insert encodes a deduced protein of 277 amino acids, whereas the cDNA containing the insert has an alternative C-terminal sequence that is 74 amino acids longer. The similarity between the HSJ1 and DnaJ proteins is restricted to the N-terminal region. In addition, the N-terminal and central regions of the HSJ1 proteins share sequence similarity with those regions of SIS1, a yeast homolog of DnaJ. Western blot analysis of human brain homogenates using antibodies against HSJ1 detected proteins with apparent molecular masses of approximately 42 and 36 kD. Northern blot analysis detected 3.0- and 2.0-kb HSJ1 transcripts in human brain; no HSJ1 expression was found in the other tissues examined. RNase protection analysis showed that HSJ1 is expressed almost exclusively in the brain, with the highest levels in the frontal cortex and hippocampus. In situ hybridization of human brain sections detected HSJ1 mRNA mainly in the neuronal layers.

DNAJB2 isoform b is more abundant in brain than isoform a (Borrell-Pages et al., 2006).

▼ Gene Structure
The DNAJB2 gene contains 10 exons and encodes 2 main transcripts, isoform a, encoded by exons 2-10, and isoform b, encoded by exons 2-9 (summary by Blumen et al., 2012).

▼ Mapping
The International Radiation Hybrid Mapping Consortium mapped the HSJ1 gene to chromosome 2 (Cda0vf12).

▼ Gene Function
Borrell-Pages et al. (2006) found that Hsj1 proteins protected rat striatal neurons from polyQ-huntingtin (613004)-induced cell death. Hsj1a reduced intranuclear inclusions by acting as a typical chaperone that unfolds misfolded proteins, whereas Hsj1b had a neuroprotective effect by inhibiting cell death without any major effects in polyQ-huntingtin aggregation. Hsj1b mediated its beneficial effects by promoting release of BDNF (113505) from the Golgi apparatus in neuronal cells. Postmortem brain tissue from patients with Huntington disease (HD; 143100) showed significantly decreased levels of HSJ1b compared to controls. Treatment with cystamine, a transglutaminase inhibitor, increased Hsj1b levels and increased levels of BDNF in mouse neuronal cells and in a mouse model of Huntington disease and showed a neuroprotective effect. Treatment of rodent and primate models of HD with cystamine and cysteamine resulted in a transient increase in peripheral blood levels of BDNF in these animals.

Blumen et al. (2012) demonstrated that cotransfection of either DNAJB2 isoform reduced aggregation of mutant SOD1 (147450) in motor neuron-like cells. The antiaggregating effect was even more pronounced when both isoforms were transfected into these cells. These findings indicated that DNAJB2 has a neuroprotective effect in motor neurons.

▼ Molecular Genetics
In 3 sibs, born of Moroccan Jewish Israeli parents, with autosomal recessive distal spinal muscular atrophy-5 (DSMA5; 614881), Blumen et al. (2012) identified a homozygous splice site mutation in the DNAJB2 gene (604139.0001). The mutation was identified by homozygosity mapping followed by candidate gene sequencing. Patient fibroblasts showed decreased levels of DNAJB2 isoform b compared to controls, and nuclear and cytoplasmic expression of DNAJB2 was decreased compared to controls. Transfection of the DNAJB2 truncating mutant into motor neuron-like cells did not reduce aggregation of mutant SOD1, whereas transfection of wildtype DNAJB2 suppressed aggregation. The findings indicated that loss of function of DNAJB2 play a determining role in this disorder. The disorder was characterized by young adult onset of slowly progressive distal muscle weakness and atrophy resulting in gait impairment and loss of reflexes. Sensation and cognition were not impaired. Direct sequencing of coding exons of the DNAJB2 gene in 40 additional patients with distal spinal muscular atrophy did not identify any mutations.

In 2 sisters, born of consanguineous Turkish parents, with DSMA5, Gess et al. (2014) identified a homozygous splice site mutation in the DNAJB2 gene (604139.0002). The mutation was demonstrated to result in a loss of protein expression. The proband was from a larger cohort of 90 patients with autosomal recessive hereditary neuropathies who underwent genetic studies.

In 2 Austrian sisters with young adult onset of DSMA5 and sensory neuropathy, Gess et al. (2014) identified a homozygous missense mutation in the DNAJB2 gene (Y5C; 604139.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in several large public databases. However, functional studies were not performed. The proband was from a larger cohort of 90 patients with autosomal recessive inherited neuropathies who underwent genetic studies. The Y5C mutation had previously been found in this family by Schabhuttl et al. (2014), who reported the family as family HMNS-R1. The findings expanded the phenotype associated with DNAJB2 mutations to include sensory neuropathy. Gess et al. (2014) diagnosed the Austrian sisters with Charcot-Marie-Tooth disease type 2.

▼ ALLELIC VARIANTS ( 3 Selected Examples):

.0001 SPINAL MUSCULAR ATROPHY, DISTAL, AUTOSOMAL RECESSIVE, 5
DNAJB2, IVS5DS, G-A, +1
In 3 sibs, born of Moroccan Jewish Israeli parents, with autosomal recessive distal spinal muscular atrophy-5 (DSMA5; 614881), Blumen et al. (2012) identified a homozygous G-to-A transition in the donor splice site of exon 5 of the DNAJB2 gene (352+1G-A), resulting in the addition of 2 aberrant transcripts containing partial or complete retention of exon 5 and resulting in premature termination. However, the wildtype DNAJB2 transcript was also detected in patient fibroblasts. The unaffected mother was heterozygous for the mutation, which was not found in 400 European or 120 Moroccan Jewish control chromosomes. The mutation was identified by homozygosity mapping followed by candidate gene sequencing. Patient fibroblasts showed decreased levels of DNAJB2 isoform b compared to controls and absent expression of isoform a. Immunofluorescent studies showed decreased nuclear and cytoplasmic expression of DNAJB2 in patient fibroblasts compared to controls. Transfection of the DNAJB2 truncating mutant into motor neuron-like cells did not reduce aggregation of mutant SOD1 (147450), whereas transfection of wildtype DNAJB2 suppressed aggregation. The findings indicated that loss of function of DNAJB2 play a determining role in this disorder.

.0002 SPINAL MUSCULAR ATROPHY, DISTAL, AUTOSOMAL RECESSIVE, 5
DNAJB2, IVS4DS, G-A, +1
In 2 sisters, born of consanguineous Turkish parents, with autosomal recessive distal spinal muscular atrophy-5 (DSMA5; 614881), Gess et al. (2014) identified a homozygous G-to-A transition in intron 4 of the DNAJB2 gene (c.229+1G-A). The mutation, which was found by direct sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases, in an in-house database of over 2,000 exomes, or in 96 Turkish control individuals. Patient leukocytes showed an abnormal transcript with a retained intron 4, which introduced a premature stop codon at position 102 in intron 4. Western blot analysis of patient fibroblasts showed loss of both isoforms of the DNAJB2 protein. The findings were consistent with a loss of function.

.0003 SPINAL MUSCULAR ATROPHY, DISTAL, AUTOSOMAL RECESSIVE, 5
DNAJB2, TYR5CYS
In 2 Austrian sisters with young adult onset of autosomal recessive distal spinal muscular atrophy-5 and sensory neuropathy (DSMA5; 614881), Gess et al. (2014) identified a homozygous c.14A-G transition in the DNAJB2 gene, resulting in a tyr5-to-cys (Y5C) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases, or in an in-house database of over 2,000 exomes. Functional studies of the variant were not performed. The Y5C mutation had previously been found in this family by Schabhuttl et al. (2014), who reported the family as family HMNS-R1. The findings expanded the phenotype associated with DNAJB2 mutations to include sensory neuropathy. Gess et al. (2014) diagnosed the sisters with Charcot-Marie-Tooth disease type 2.

Tags: 2q35