A novel dominant D109A CRYAB mutation in a family with myofibrillar myopathy affects αB-crystallin structure

Fichna, Jakub Piotr; Potulska‐Chromik, Anna; Miszta, Przemysław; Redowicz, Maria Jolanta; Kamińska, Anna; Żekanowski, Cezary; Filipek, Sławomir

doi:10.1016/j.bbacli.2016.11.004

Cited by 43 publications

(43 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additional dominant missense and truncating variants (Table 5) have been identified in patients with comparable combination of phenotypes, i.e., myopathy and variable cardiac involvement, often together with cataracts [223][224][225][226][227], and in some cases with isolated cardiomyopathy [228,229]. The myopathy phenotypes show variability in age of onset and muscle involvement: the weakness may be widespread-including trunk, neck, velopharyngeal, and respiratory muscles in addition to proximal and distal limb muscles-or show a more limited distal involvement [222][223][224][225][226][227]. Neuropathy has been reported in isolated cases [223].…”

Section: Neuromuscular Diseases Due To Cryab Mutationsmentioning

confidence: 99%

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Sarparanta

Jonson

Kawan

et al. 2020

IJMS

View full text Add to dashboard Cite

Skeletal muscle and the nervous system depend on efficient protein quality control, and they express chaperones and cochaperones at high levels to maintain protein homeostasis. Mutations in many of these proteins cause neuromuscular diseases, myopathies, and hereditary motor and sensorimotor neuropathies. In this review, we cover mutations in DNAJB6, DNAJB2, αB-crystallin (CRYAB, HSPB5), HSPB1, HSPB3, HSPB8, and BAG3, and discuss the molecular mechanisms by which they cause neuromuscular disease. In addition, previously unpublished results are presented, showing downstream effects of BAG3 p.P209L on DNAJB6 turnover and localization.

show abstract

Section: Neuromuscular Diseases Due To Cryab Mutationsmentioning

confidence: 99%

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Sarparanta

Jonson

Kawan

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Our structural/functional analysis indicates a deleterious effect of CRYAB ‐p.D109G (strong criterion), which is a novel missense mutation at this amino acid position. Two other pathogenic mutations have been described previously at this codon (moderate criterion): p.D109A (Fichna et al., ) and p.D109H (Sacconi et al., ). Of note, in six p.D109A mutation carriers (three males and three females) of the affected family, all but one had an isolated myofibrillar myopathy (MFM) without cardiac involvement.…”

mentioning

confidence: 91%

“…H). Of note, this region is a hot spot for missense mutations in patients with different skeletal and cardiac myopathies (Fichna et al., ; Sacconi et al., ; Vicart et al., ).…”

mentioning

confidence: 99%

“…Of note, in six p.D109A mutation carriers (three males and three females) of the affected family, all but one had an isolated myofibrillar myopathy (MFM) without cardiac involvement. An additional DCM was only reported in a female p.D109A mutation carrier presenting a late onset of the disease (55 years) and respiratory failure at the age of 56 years (Fichna et al., ). The mutation p.D109H was reported in five members of a French family.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The novel αB‐crystallin ( CRYAB ) mutation p.D109G causes restrictive cardiomyopathy

et al. 2017

View full text Add to dashboard Cite

Restrictive cardiomyopathy (RCM) is a rare heart disease characterized by diastolic dysfunction and atrial enlargement. The genetic etiology of RCM is not completely known. We identified by a next-generation sequencing panel the novel CRYAB missense mutation c.326A>G, p.D109G in a small family with RCM in combination with skeletal myopathy with an early onset of the disease. CRYAB encodes αB-crystallin, a member of the small heat shock protein family, which is highly expressed in cardiac and skeletal muscle. In addition to in silico prediction analysis, our structural analysis of explanted myocardial tissue of a mutation carrier as well as in vitro cell transfection experiments revealed abnormal protein aggregation of mutant αB-crystallin and desmin, supporting the deleterious effect of this novel mutation. In conclusion, CRYAB appears to be a novel RCM gene, which might have relevance for the molecular diagnosis and the genetic counseling of further affected families in the future.

show abstract

“…47 Mutation at either site in the salt bridge frequently leads to malfunction and disease. [46][47][48][49] For example, the R120G mutant is genetically linked to desmin-related myopathy, 50 while mutation of αB Asp109 is associated with myofibrillar myopathy 51 and cardiomyopathy. 52 To probe the structural consequences of αB Asp109 isomerization on the dimer interface of αB, in silico mutation and MD simulations were utilized, after parameterizing the force field for the isomeric amino acids.…”

Section: Phosphorylation Is Precluded By Epimerization Of αB Ser59 Anmentioning

confidence: 99%

Structural and Functional Consequences of Age-Related Isomerization in α-Crystallins

Lyon

Riggs

Collier

et al. 2018

Preprint

View full text Add to dashboard Cite

Long-lived proteins are subject to spontaneous degradation and may accumulate a range of modifications over time, including subtle alterations such as isomerization. Recently, tandem-mass spectrometry approaches have enabled the identification and detailed characterization of such peptide isomers, including those differing only in chirality. However, the structural and functional consequences of these perturbations remain largely unexplored. Here we examine the site-specific impact of isomerization of aspartic acid and epimerization of serine in human αAand αB-crystallin.From a total of 81 sites of modification identified in aged eye lenses, four ( αB Ser59, αA Ser162, αB Asp62, αB Asp109) map to crucial oligomeric interfaces. To characterize the effect of isomerization on quaternary assembly, molecular dynamics calculations and native mass spectrometry experiments were performed on recombinant forms of αAand αB-crystallin that incorporate, or mimic, isomerized residues. In all cases, oligomerization is significantly affected, with epimerization of a single serine residue ( αA Ser162) sufficing to weaken inter-subunit binding dramatically. Furthermore, phosphorylation of αB Ser59, known to play an important regulatory role in oligomerization, is severely inhibited by serine epimerization and altered by isomerization of nearby αB Asp62. Similarly, isomerization of αB Asp109 disrupts a vital salt-bridge with αB Arg120, a loss previously shown to yield aberrant oligomerization and aggregation in several disease variants. Our results illustrate how isomerization of amino-acid residues, which may seem like a minor structural perturbation, can have profound consequences on protein assembly and activity by disrupting specific hydrogen bonds and salt bridges. Significance StatementProteins play numerous critical roles in our bodies but suffer damage with increasing age. For example, isomerization is a spontaneous post-translational modification that alters the threedimensional connectivity of an amino acid, yet remains invisible to traditional proteomic experiments.Herein, radical-based fragmentation was used for isomer identification while molecular dynamics and native mass spectrometry were utilized to assess structural consequences. The results demonstrate that isomerization disrupts both oligomeric assembly and phosphorylation in the α-crystallins, which are long-lived proteins in the lens of the eye. The loss of function associated with these modifications is likely connected to age-related diseases such as cataract and neurodegenerative disorders, while the methodologies we present represent a framework for structure-function studies on other isomerized proteins.

show abstract

A novel dominant D109A CRYAB mutation in a family with myofibrillar myopathy affects αB-crystallin structure

Cited by 43 publications

References 52 publications

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

The novel αB‐crystallin ( CRYAB ) mutation p.D109G causes restrictive cardiomyopathy

Structural and Functional Consequences of Age-Related Isomerization in α-Crystallins

Contact Info

Product

Resources

About