Alternative titles; symbols
HGNC Approved Gene Symbol: DNAJB6
ICD10CM: G71.031;
Cytogenetic location: 7q36.3 Genomic coordinates (GRCh38) : 7:157,337,004-157,417,439 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q36.3 | Muscular dystrophy, limb-girdle, autosomal dominant 1 | 603511 | Autosomal dominant | 3 |
DNAJB6 belongs to the evolutionarily conserved DNAJ/HSP40 family of proteins, which regulate molecular chaperone activity by stimulating ATPase activity. DNAJ proteins may have up to 3 distinct domains: a conserved 70-amino acid J domain, usually at the N terminus; a glycine/phenylalanine (G/F)-rich region; and a cysteine-rich domain (Ohtsuka and Hata, 2000).
By database searching for DNAJ-like proteins, Seki et al. (1999) identified and subsequently cloned DNAJB6, which they called MRJ, from a human fetal brain cDNA library. The deduced 241-amino acid protein has a calculated molecular mass of 37 kD. DNAJB6 contains an N-terminal J domain followed by a glycine-rich region, but does not contain a cysteine-rich region. The protein shares 94% sequence identity with the mouse homolog. RT-PCR analysis detected ubiquitous expression of DNAJB6.
By searching EST databases for J domain-containing proteins, Ohtsuka and Hata (2000) identified 10 mouse and human DNAJ homologs, including mouse DnajB6. The predicted type II transmembrane protein contains 242 amino acids.
By Northern blot analysis, Chuang et al. (2002) found that the expression of human DNAJB6 was highest in brain and much weaker in all other tissues examined. Within brain, expression was highest in hippocampus and thalamus, and lower in amygdala, substantia nigra, corpus callosum, and caudate nucleus.
Sarparanta et al. (2012) found expression of the DNAJB6 gene at Z discs in human skeletal muscle.
DNAJB6 is expressed as 2 isoforms with distinct cellular localizations: DNAJB6a (326 residues) localizes to the nucleus, whereas DNAJB6b (242 residues) localizes to both the nucleus and the cytoplasm. Bengoechea et al. (2015) found expression of both isoforms in human and mouse skeletal muscle. In mouse muscle, Dnajb6a showed nuclear localization and Dnajb6b was incorporated into the sarcomere.
Chuang et al. (2002) demonstrated that full-length DNAJB6 stimulated ATP hydrolysis by HSP70 (see HSPA1A, 140550) in a time- and concentration-dependent manner. Both an N-terminal fragment (amino acids 1-109) and a C-terminal fragment (amino acids 108-241) enhanced the ATPase activity of HSP70. Human embryonic kidney 293 cells transfected with mutant huntingtin (HTT; 613004) N terminus exhibited puncta or aggregates of mutant huntingtin distributed throughout the cytoplasm and nucleus. Coexpression of DNAJB6 delayed aggregate formation and significantly reduced caspase-3 (CASP3; 600636) activation induced by mutant huntingtin. DNAJB6 also inhibited CASP3 activity augmented by the apoptotic reagent staurosporine.
By PCR analysis of a human/rodent monochromosomal hybrid cell panel and a radiation hybrid panel, Seki et al. (1999) mapped the DNAJB6 gene to chromosome 11q25. However, Gross (2011) mapped the DNAJB6 gene to chromosome 7q36.3 based on alignment of the DNAJB6 sequence (GenBank BC002446) with the genomic sequence (GRCh37).
In affected members of a Caucasian family with autosomal dominant limb-girdle muscular dystrophy (LGMDD1; 603511), earlier designated LGMD1E, Harms et al. (2012) identified a heterozygous mutation in the DNAJB6 gene (F93L; 611332.0001). The mutation was identified by whole-genome exome capture followed by next-generation sequencing. Sequencing of the DNAJB6 gene in 13 additional probands with a similar disorder revealed a second mutation (P96R; 611332.0002) in affected members of an African American family with an autosomal dominant myopathy. Both families had adult-onset of slowly progressive muscle weakness resulting in loss of ambulation after about 20 years, although 1 family had greater involvement of the proximal muscles and the other had greater involvement of the distal muscles. Neither family had cardiac or pulmonary involvement.
Sarparanta et al. (2012) identified 4 different heterozygous mutations in the DNAJB6 gene (611332.0001, 611332.0003-611332.0005) in affected members of 9 families with LGMD1E. Five of the families were of Finnish origin (Sandell et al., 2010 and Hackman et al., 2011) and carried the same mutation (611332.0003). Two additional families had previously been reported by Speer et al. (1995, 1999). Electron microscopy of patient muscle showed Z disc myofibrillar disintegration and autophagic rimmed vacuoles. DNAJB6 was detected in protein accumulations together with its known ligands MLF1 (601402) and HSPA8 (600816). However, DNAJB6 appeared more in the periphery of the protein accumulations, in contrast to more pronounced colocalization seen in myotilinopathies. Three of the mutations resulted in a phe93-to-leu (F93L) substitution at a highly conserved residue. In vitro functional expression studies showed that the mutations increased the half-life of DNAJB6, extended this effect to the wildtype protein, and reduced the protective antiaggregation effect of DNAJB6. The mutations showed a dominant toxic effect mediated specifically by the cytoplasmic isoform of DNAJB6. The compromised antiaggregation function may lead to impaired protein quality control and accumulation of other proteins. DNAJB6 was found to interact with members of the chaperone-assisted selective autophagy (CASA) complex, including a myofibrillar myopathy (MFM6; 612954)-related protein BAG3 (603883). The findings indicated that LGMD1E is mediated by defective chaperone function, resulting in insufficient maintenance of sarcomeric structures or defective clearance of misfolded sarcomeric proteins.
Stein et al. (2014) noted that all known LGMD1E mutations localized in the conserved G/F domain of DNAJB6. Using yeast-human chimeric proteins, they found that these DNAJB6 mutants were variably deficient in resolving prion protein aggregates in yeast, with strongest effect shown by the F89I mutation (611332.0005) or deletion of the entire G/F domain. TDP43 (TARDBP; 605078) has a domain similar to that found in yeast prion proteins; in addition, TDP43 aggregates into stress granules during heat shock and accumulates in LGMD1E patient muscle. Stein et al. (2014) showed that HeLa cells expressing TDP43 formed nuclear stress bodies during heat shock, and that wildtype, but not G/F mutant, DNAJB6 resolved these stress bodies following recovery from heat shock. LGMD1E patient fibroblasts with the F93L substitution (see 611332.0001) also showed delayed dissolution of TDP43 nuclear stress bodies following recovery from heat shock.
In affected members of a large family with LGMD1E, Ruggieri et al. (2015) identified a heterozygous missense mutation in the DNAJB6 gene (F100V; 611332.0006). The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Direct Sanger sequencing of the DNAJB6 gene in 63 patients with sporadic occurrence of a similar disorder identified 4 with de novo heterozygous mutations (611332.0003; 611332.0007-611332.0009), thus accounting for 6.4% of the cohort. All the mutations affected the conserved G/F domain, although direct functional studies were not performed. There was some evidence for a genotype/phenotype correlation: proximal G/F mutations were associated with proximal myopathy, whereas distal G/F mutations were associated with distal-onset myopathy. The mutations were predicted to affect the G/F-J interaction in different ways.
By exome sequencing in a Hungarian family with a late-onset, mild, and slowly progressive form of LGMDD1, Zima et al. (2020) identified a heterozygous missense mutation in the DNAJB6 gene (F91V; 611332.0010). The authors noted that previous mutations involving the phe91 residue (611332.0007 and 611332.0008) were associated with a more severe form of the disease.
In zebrafish, Sarparanta et al. (2012) found expression of the Dnajb6 gene as early as the embryonic 5-somite stage. Injection of 2-cell embryos with a splice-blocking morpholino resulted in a reproducible muscle fiber detachment phenotype. Detachment of slow fibers from their insertion sites at the vertical myoseptum was evident as early as 2 days after fertilization, suggesting adhesion failure with mechanical load. These data indicated that loss of Dnajb6 leads to defects in muscle integrity. Injection of the human mutants F93L (see, e.g., 611332.0001) or F89I (611332.0005) also caused the muscular phenotype, and coinjection with wildtype Dnajb6 showed enhanced severity of the phenotype, consistent with a dominant-negative effect.
Bengoechea et al. (2015) found that transgenic mice expressing the LGMD1E-associated DNAJB6 F93L mutation (611332.0001) in the Dnajb6b isoform had early lethality due to profound muscle weakness, whereas mice with the mutation in the Dnajb6a isoform were unaffected after 1 year. Muscle biopsy of affected mice showed localization of mutant Dnajb6b in the Z-disc, myofibrillar disorganization, desmin and keratin inclusions, and abnormal sarcoplasmic protein aggregations of RNA-binding proteins.
In affected members of a Caucasian family with autosomal dominant limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), Harms et al. (2012) identified a heterozygous 277T-C transition in the DNAJB6 gene, resulting in a phe93-to-leu (F93L) substitution in a highly conserved residue within the G/F domain. The mutation was not found in over 3,000 controls. Five affected individuals had onset of limb-girdle weakness beginning in the fourth decade. The disorder was manifest as difficulty in climbing stairs or getting up from the floor. In 2 patients, the quadriceps muscles were less affected than the hamstrings. None had cardiac, pulmonary, or bulbar involvement. The disorder was slowly progressive, but a wheelchair was required after about 20 years. Skeletal muscle biopsy from 3 patients showed a chronic myopathy with rimmed vacuoles, variation in fiber size, and internal nuclei. Immunostaining showed TDP43 (605078)- and DNAJB6-positive accumulation in multiple fibers; some inclusions were around and within the vacuoles. Serum creatine kinase was increased, and EMG showed clear myopathic changes.
Sarparanta et al. (2012) identified a heterozygous 277T-C transition in 4 affected individuals from an Italian family with LGMDD1. The F93L substitution can also be caused by a 279C-G transversion (611332.0003) and a 279C-A transversion (611332.0004).
In affected members of an African American family with limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), Harms et al. (2012) identified a heterozygous 287C-G transversion in the DNAJB6 gene, resulting in a pro96-to-arg (P96R) substitution at a highly conserved residue in the G/F domain. The mutation was not found in over 3,000 controls. Three affected individuals from an African American family had a distal-predominant myopathy with onset between ages 18 and 35 years. Weakness began in the lower limbs, often manifest as tripping, but progressed to include the hands and proximal legs with loss of ambulation after about 20 to 40 years. There was no cardiac or pulmonary involvement.
In 16 affected members from 5 Finnish families with limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), previously reported by Sandell et al. (2010) and Hackman et al. (2011), Sarparanta et al. (2012) identified a heterozygous 279C-G transversion in exon 5 of the DNAJB6 gene, resulting in a phe93-to-leu (F93L) substitution at a highly conserved residue in the G/F domain. The mutation was not found in 202 Finnish, 104 Italian, or 215 U.S. control individuals. The F93L substitution can also be caused by a 277T-C transition (611332.0001) and a 279C-A transversion (611332.0004).
In a 57-year-old man (patient 3s) with sporadic occurrence of LGMD1E and onset at age 45, Ruggieri et al. (2015) identified a de novo heterozygous c.279C-G transversion (c.279C-G, NC_000007.14) in the DNAJB6 gene. The mutation was found by Sanger sequencing. He had proximal and distal muscle weakness affecting only the lower limbs and remained ambulatory.
In 8 affected individuals of an Italian family with limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), Sarparanta et al. (2012) identified a heterozygous 279C-A transversion in exon 5 of the DNAJB6 gene, resulting in a phe93-to-leu (F93L) substitution at a highly conserved residue in the G/F domain. The F93L substitution can also be caused by a 277T-C transition (611332.0001) and a 279C-G transversion (611332.0003). The mutation was not found in 202 Finnish, 104 Italian, or 215 U.S. control individuals.
In affected members of 2 families from the U.S. with limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), originally reported by Speer et al. (1995, 1999), Sarparanta et al. (2012) identified a heterozygous c.265T-A transversion (which they referred to as c.267T-A) in the DNAJB6 gene, resulting in a phe89-to-ile (F89I) substitution at a highly conserved residue in the G/F domain. The mutation was not found in 202 Finnish, 104 Italian, or 215 U.S. control individuals.
In affected members of an American family with LGMD1E, Couthouis et al. (2014) identified a heterozygous c.265T-A transversion in the DNAJB6 gene, resulting in a phe89-to-ile (F89I) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder. It was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing project databases. Couthouis et al. (2014) stated that the mutation was the same as that identified by Sarparanta et al. (2012). Haplotype analysis determined that the mutation arose independently in the families reported by Couthouis et al. (2014) and Sarparanta et al. (2012), suggesting that it may be a mutation hotspot. Functional studies of the variant were not performed.
In affected members of a large Italian family with limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), originally reported by Servidei et al. (1999), Ruggieri et al. (2015) identified a heterozygous c.298T-G transversion in the DNAJ6 gene, resulting in a phe100-to-val (F100V) substitution at a highly conserved residue in the G/F domain. The mutation, which was found using a combination of linkage analysis and exome sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 142), 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. One 30-year-old clinically unaffected family member also carried the mutation. The distribution of muscle weakness in affected family members tended to be more distal than proximal.
In a 39-year-old woman (patient 1s) with sporadic limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), Ruggieri et al. (2015) identified a de novo heterozygous c.271T-A transversion (c.271T-A, NC_000007.14) in the DNAJ6 gene, resulting in a phe91-to-ile (F91I) substitution at highly conserved residue in the G/F domain. Functional studies of the variant were not performed. The patient had onset at age 16 years and severe involvement of the proximal and distal muscles of the upper and lower limbs resulting in loss of ambulation at age 30.
In a 59-year-old woman (patient 2s) with sporadic limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), Ruggieri et al. (2015) identified a de novo heterozygous c.273C-G transversion (c.273C-G, NC_000007.14) in the DNAJ6 gene, resulting in a phe91-to-leu (F91L) substitution at a highly conserved residue in the G/F domain. Functional studies of the variant were not performed. The patient had a severe form of the disorder, with onset at age 11 years, proximal and distal involvement of the upper and lower limbs, loss of ambulation at age 40, dysphagia, dysarthria, and late-onset respiratory difficulties.
In a 39-year-old woman (patient 4s) with sporadic limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), Ruggieri et al. (2015) identified a de novo heterozygous G-to-A transition (c.346+5G-A) in a consensus splice site sequence of the DNAJ6 gene. Analysis of patient cells showed that the mutation resulted in the skipping of exon 5 and absence of the entire G/F domain. Additional functional studies of the variant were not performed. The patient had a severe phenotype, with onset at age 6 years, proximal and distal involvement of the upper and lower limbs, and loss of ambulation at age 37.
By exome sequencing in a Hungarian family with a late-onset, mild, and slowly progressive form of autosomal dominant limb-girdle muscular dystrophy-1 (LGMDD1; 603511), Zima et al. (2020) identified a heterozygous c.271T-G transversion (c.271T-G, NM_005494.2) in the DNAJ6 gene, resulting in a phe91-to-val (F91V) substitution at a highly conserved residue. The family had a milder course than that reported in patients with LGMDD1 with variants at the same residue (611332.0007; 611332.0008). Symptoms in the Hungarian family were first reported in the third and fourth decade of life in 2 males, and 1 female in the family was asymptomatic in her early 60s with only mild features on muscle biopsy and MRI. The authors raised the question of whether this could be a disease with sex-influenced expression.
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