Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy

Sarparanta, J.; Jonson, Per Harald; Golzio, Christelle; Sandell, Satu; Luque, H.; Screen, Mark; McDonald, Kristin; Stajich, Jeffrey M.; Mahjneh, Ibrahim; Vihola, Anna; Raheem, Olayinka; Penttilä, Sini; Lehtinen, Sara; Huovinen, Sanna; Palmio, Johanna; Tasca, Giorgio; Ricci, Enzo; Hackman, Peter; Hauser, Michael A.; Katsanis, Nicholas; Udd, Bjarne

doi:10.1038/ng.1103

Cited by 231 publications

(341 citation statements)

References 36 publications

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“…Impairment of CASA in patients and animal models causes muscular dystrophy and cardiomyopathy. [6][7][8] Specifically, mutations in the CASA component BAG3 cause myofibrillar myopathy. Furthermore, DNAJB6 (associated with limb girdle muscular dystrophy 1D [LGMD1D]) interacts with members of the CASA complex, including BAG3.…”

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confidence: 99%

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Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy

et al. 2016

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Objective: To report novel disease and pathology due to HSPB8 mutations in 2 families with autosomal dominant distal neuromuscular disease showing both myofibrillar and rimmed vacuolar myopathy together with neurogenic changes.Methods: We performed whole-exome sequencing (WES) in tandem with linkage analysis and candidate gene approach as well as targeted next-generation sequencing (tNGS) to identify causative mutations in 2 families with dominant rimmed vacuolar myopathy and a motor neuropathy. Pathogenic variants and familial segregation were confirmed using Sanger sequencing.Results: WES and tNGS identified a heterozygous change in HSPB8 in both families: c.421A . G p.K141E in family 1 and c.151insC p.P173SfsX43 in family 2. Affected patients had a distal myopathy that showed myofibrillar aggregates and rimmed vacuoles combined with a clear neurogenic component both on biopsy and neurophysiologic studies. MRI of lower limb muscles demonstrated diffuse tissue changes early in the disease stage progressing later to fatty replacement typical of a myopathy. Conclusion:We expand the understanding of disease mechanisms, tissue involvement, and phenotypic outcome of HSPB8 mutations. HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex previously only associated with Charcot-Marie-Tooth type 2L (OMIM 60673) and distal hereditary motor neuronopathy type IIa. However, we now demonstrate that patients can develop a myopathy with histologic features of myofibrillar myopathy with aggregates and rimmed vacuoles, similar to the pathology in myopathies due to gene defects in other compounds of the CASA complex such as BAG3 and DNAJB6 after developing the early neurogenic effects. Mutations in the small heat shock protein 22 gene (HSPB8, also called HSP22) located on chromosome 12q24.23 are associated with Charcot-Marie-Tooth type 2L (CMT2L) (OMIM 60673) 1 and distal hereditary motor neuronopathy type IIa (dHMN2A). 2 HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex, a vital part of the cellular protein quality control system in mechanically strained cells and tissues such as skeletal muscle, heart, and lung.3-5 HSPB8 has not been previously associated with a myopathy. The CASA complex comprises the molecular chaperones HSPA8 and HSPB8 and the cochaperones BAG3 and STUB1. 5 In muscle, CASA has a specific role in maintenance of the Z-disk and protein turnover.6,7 CASA mediates degradation of the actin cross-linking protein

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confidence: 99%

“…The filter-trap assay was performed essentially as described. 8 Previous laboratory investigations showed creatine kinase (CK) levels had ranged between 850 and 2,000 U/L (normal ,250 U/L). Cardiac and respiratory investigations (including an ECG, echocardiogram, and standard respiratory function tests) were within normal limits.…”

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Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy

et al. 2016

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“…Finally, our observations potentially contribute to a growing list of genetic disorders caused by isoform-specific mutations and highlight the utility of the zebrafish model in dissecting such phenomena. For example, mutations specifically affecting the cytoplasmic functions of DNAJB6 cause limb-girdle muscular dystrophy (OMIM: 611332 and 603511) by increasing the half-life (and toxicity of the isoform), 24 whereas MEIS1 (OMIM: 601739) mutations that affect one of the splice isoforms of that locus predispose to restless leg syndrome (OMIM: 612853), most likely through a subcellular distribution mechanism. 23 We cannot exclude the formal possibility that the TMEM locus generates additional transcripts that were not detectable by our experimental paradigm.…”

Section: Renal Defectsmentioning

confidence: 99%

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome

Ta‐Shma

Khan

Vivante

et al. 2017

The American Journal of Human Genetics

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Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.Whole-exome and whole-genome sequencing (WES and WGS, respectively) have accelerated the expansion of the repertoire of human loci underscoring Mendelian phenotypes to account for~3,000 human genes (15%).1 Nonetheless, the diagnostic yield remains <50%, 2-4 suggesting that the majority of disease-causing lesions are yet to be identified and that a significant fraction of this genetic burden is likely to be contributed by ultra-rare or private mutations. To contribute to the saturation of the morbid human genome as a means of improving both diagnostic value and mechanistic insight, we undertook the systematic sequencing of families affected by suspected genetic disorders, with an emphasis on congenital syndromic traits. Here, we report the genetic and functional dissection of affected individuals with a genetically undiagnosed syndrome characterized by cardiac, CNS, renal, and digit abnormalities in two unrelated consanguineous pedigrees. We show that the likely molecular cause, homozygous truncating mutations in TMEM260, affect the functions of one of the two established isoforms transcribed from this locus, thereby demonstrating the necessity of the long isoform for the development of multiple tissues. We consulted family 1, a con...

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“…In vitro protein aggregation assay was used to test for the function of the co-chaperone DNAJB6 that was shown to cause limb-girdle muscular dystrophy (53).…”

Section: R12mentioning

confidence: 99%

“…Last, co-injection of wild type and mutant mRNAs provides a test for dominant negative effects. Recent examples of the successful application of this approach include the analysis of mutations in co-chaperone DNAJB6 (53) and mutations in the RNA exosome component causing pontocerebellar hypoplasia and spinal motor neuron degeneration (56). Zebrafish model was employed with great success in characterizing multiple variants in several genes involved in ciliopathies (57).…”

Section: R12mentioning

confidence: 99%

Inferring causality and functional significance of human coding DNA variants

Sunyaev

2012

Human Molecular Genetics

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Sequencing technology enables the complete characterization of human genetic variation. Statistical genetics studies identify numerous loci linked to or associated with phenotypes of direct medical interest. The major remaining challenge is to characterize functionally significant alleles that are causally implicated in the genetic basis of human traits. Here, I review three sources of evidence for the functional significance of human DNA variants in protein-coding genes. These include (i) statistical genetics considerations such as co-segregation with the phenotype, allele frequency in unaffected controls and recurrence; (ii) in vitro functional assays and model organism experiments; and (iii) computational methods for predicting the functional effect of amino acid substitutions. In spite of many successes of recent studies, functional characterization of human allelic variants remains problematic.

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Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy

Cited by 231 publications

References 36 publications

Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy

Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome

Inferring causality and functional significance of human coding DNA variants

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