c.3G&gt;A mutation in the CRYAB gene that causes fatal infantile hypertonic myofibrillar myopathy in the Chinese population

Gu²,

et al. 2023

Front. Pediatr.

BackgroundFatal infantile hypertonic myofibrillar myopathy (FIHMM) is an autosomal recessive hereditary disease characterized by amyotrophy, progressive flexion contracture and ankylosis of the trunk and limb muscles, apnea and respiratory failure, and increased creatine phosphate levels. It is caused by mutations in the CRYAB gene, and only around 18 cases including genetic mutations have been reported worldwide. All patients with FIHMM develop respiratory distress, progressive stiffness of the limbs, and have a poor prognosis. However, no effective treatment for CRYAB-associated respiratory failure has been reported. Here, we report a case of FIHMM with a novel heterozygous missense mutation.Case PresentationA 2-year-old female developed scoliosis of the lumbar spine and restrictive ventilatory dysfunction in infancy. She was admitted to the hospital with labored breathing on the third day after the second injection of inactivated poliomyelitis vaccine. Acute respiratory failure, pneumothorax, and cardiac arrest arose in the patient during hospitalization, and progressive stiffness of the trunk and limb muscles appeared, accompanied by obvious abdominal distension and an increase in phosphocreatine kinase levels. Screenings for genetic metabolic diseases in the blood and urine were normal. Electromyography revealed mild myogenic damage. A muscle biopsy indicated the accumulation of desmin, α-crystallin, and myotilin in the musculus biceps brachii, and dense granules were observed in muscle fibers using electron microscopy. Mutation analysis of CRYAB revealed a novel heterozygous missense mutation in the proband, c.302A > C (p.His101Pro) and c.3G > A (p.Met1Ile), which inherited from her asymptomatic, heterozygous carrier parents, respectively. The proband was finally diagnosed as FIHMM. One month after the FIHMM diagnosis, the child died of respiratory failure.ConclusionWe report a case of FIHMM with a novel heterozygous missense mutation of CRYAB. This finding might improve our understanding of FIHMM and highlight a novel mutation in the Chinese population.

Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Case report: Fatal infantile hypertonic myofibrillar myopathy with compound heterozygous mutations in the CRYAB gene

Gu²,

et al. 2023

Front. Pediatr.

“…Conversely, HSPB5 deficiency or complete loss of function associate to multisystem disorders in which eye lenses and skeletal and heart muscles might also be affected. This is the case of homozygous HSPB5 M1X and S21Afs*24 mutations, linked to infantile hypertonic myofibrillar myopathy (MFM), a severe and rare form of myopathy, often accompanied by cardiomyopathy and cataracts (Del Bigio et al, 2011;Ma et al, 2019;Lu et al, 2021). The HSPB5 M1X mutation determines the loss of the ATG starting codon and it likely associates with loss of HSPB5 protein.…”

Section: Hspb4 and Hspb5mentioning

confidence: 99%

Insights on Human Small Heat Shock Proteins and Their Alterations in Diseases

Tedesco

Cristofani

Ferrari

et al. 2022

Front. Mol. Biosci.

The family of the human small Heat Shock Proteins (HSPBs) consists of ten members of chaperones (HSPB1-HSPB10), characterized by a low molecular weight and capable of dimerization and oligomerization forming large homo- or hetero-complexes. All HSPBs possess a highly conserved centrally located α-crystallin domain and poorly conserved N- and C-terminal domains. The main feature of HSPBs is to exert cytoprotective functions by preserving proteostasis, assuring the structural maintenance of the cytoskeleton and acting in response to cellular stresses and apoptosis. HSPBs take part in cell homeostasis by acting as holdases, which is the ability to interact with a substrate preventing its aggregation. In addition, HSPBs cooperate in substrates refolding driven by other chaperones or, alternatively, promote substrate routing to degradation. Notably, while some HSPBs are ubiquitously expressed, others show peculiar tissue-specific expression. Cardiac muscle, skeletal muscle and neurons show high expression levels for a wide variety of HSPBs. Indeed, most of the mutations identified in HSPBs are associated to cardiomyopathies, myopathies, and motor neuropathies. Instead, mutations in HSPB4 and HSPB5, which are also expressed in lens, have been associated with cataract. Mutations of HSPBs family members encompass base substitutions, insertions, and deletions, resulting in single amino acid substitutions or in the generation of truncated or elongated proteins. This review will provide an updated overview of disease-related mutations in HSPBs focusing on the structural and biochemical effects of mutations and their functional consequences.

“…In the following years, other HSPB5 mutations leading to DRM have been identified, such as Gln151X and Pro155ArgfsTer163 [ 28 ], Gly153Ser [ 26 ], Ser115ProfsTerf129 [ 22 ], Ser21AlafsX24 [ 20 ], as well as Asp109 His [ 27 ], Asp109Ala [ 21 ], and Ala172ProfsTer14 [ 113 ], and only recently the mutation c.3G > A, classified as a new type of early-onset MFM [ 31 ].…”

Section: Pathological Roles Of Hspb5 In Skeletal and Cardiac Musclementioning

confidence: 99%

“…HSPB5 is expressed constitutively in a variety of tissues including lens, skeletal muscle, heart, brain, lung, and kidney, as well as in extracellular fluids where it exhibits pleiotropic roles [ 14 , 15 , 16 , 17 , 18 ]. Moreover, scientific evidence highlights the importance of this protein in maintaining cellular functions; indeed, either HSPB5 overexpression or its deleterious mutations are found in a number of known disorders [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Alpha B-Crystallin in Muscle Disease Prevention: The Role of Physical Activity

Dimauro

Caporossi

2022

Molecules

HSPB5 or alpha B-crystallin (CRYAB), originally identified as lens protein, is one of the most widespread and represented of the human small heat shock proteins (sHSPs). It is greatly expressed in tissue with high rates of oxidative metabolism, such as skeletal and cardiac muscles, where HSPB5 dysfunction is associated with a plethora of human diseases. Since HSPB5 has a major role in protecting muscle tissues from the alterations of protein stability (i.e., microfilaments, microtubules, and intermediate filament components), it is not surprising that this sHSP is specifically modulated by exercise. Considering the robust content and the protective function of HSPB5 in striated muscle tissues, as well as its specific response to muscle contraction, it is then realistic to predict a specific role for exercise-induced modulation of HSPB5 in the prevention of muscle diseases caused by protein misfolding. After offering an overview of the current knowledge on HSPB5 structure and function in muscle, this review aims to introduce the reader to the capacity that different exercise modalities have to induce and/or activate HSPB5 to levels sufficient to confer protection, with the potential to prevent or delay skeletal and cardiac muscle disorders.