Molecular Genetic Pathogenesis
Because myofibrillar myopathy is caused by pathogenic variants in any of eight different genes and each disease-associated gene may have different types of pathogenic variants, the molecular pathogenesis may vary from case to case. However, in all myofibrillar myopathies, the initial pathologic change involves disintegration of the Z-disk, and all disease proteins identified to date are involved in maintaining the structural integrity of the Z-disk. Because the Z-disks are sites of tension transmission between sarcomeres, the myofibrils fall apart when the Z-disks disintegrate.
Animal models. Desmin knockout mice show normal development of cardiac and skeletal muscle but subsequently show myofiber necrosis and phagocytosis [Capetanaki et al 1997]. This model is not comparable with human cases of desminopathy in which pathogenic missense variants weaken sarcomere structure and are associated with abnormal accumulation of desmin and other proteins. Transgenic mice that produce an inactivated form of human desmin (p.Arg173_Glu179del) show desmin immunoreactive aggregates in myocardium [Muñoz-Mármol et al 1998]. Transgenic mice expressing an α-B crystallin mutated protein (p.Arg120Gly) develop a severe cardiomyopathy with abnormal accumulation of desmin and α-B crystallin in the heart; muscle pathology was not mentioned in this report [Wang et al 2001].
DES
Gene structure.
DES consists of nine exons. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. More than forty pathogenic variants including missense, frameshifting nucleotide insertion, small in-frame deletion, and splice-site variants have been reported [Goldfarb et al 2004]. See .
Table 2.
Selected DES Pathogenic Variants
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.517_537del | p.Arg173_Glu179del |
NM_001927.3
NP_001918.3
|
Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. Desmin, comprising 470 amino acids, is a constituent of intermediate filaments in cardiac and skeletal muscle linking Z-disks with each other and to the subsarcolemmal cytoskeleton.
Abnormal gene product. Expression data suggest abnormal aggregation of mutated desmin molecules in heterologous systems. Pathogenic variants may interfere with desmin assembly and filament formation [Bär et al 2006].
CRYAB
Gene structure.
CRYAB consists of three exons. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. A nonsense variant, a missense variant, and a small frameshifting deletion have been reported [Vicart et al 1998, Selcen & Engel 2003]. Recently, autosomal recessive inheritance was shown for the p.Ser115ProfsTer14 [Forrest et al 2011] and Ser21AlafsTer24 [Del Bigio et al 2011] frameshift variants. See .
Table 3.
Selected CRYAB Pathogenic Variants
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.60delC 1 | p.Ser21AlafsTer24 |
NM_001885.1
NP_001876.1
|
c.343delT 2 | p.Ser115ProfsTer14 |
c.358A>G | p.Arg120Gly |
Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
- 2.
Normal gene product. Alpha crystallin B chain (α-B crystallin) is a small heat-shock chaperone protein required for maintaining the structural integrity of desmin. It is composed of 175 amino acid residues.
Abnormal gene product. Mutated alpha crystallin B chain molecules form smaller molecular-weight polymers than wild type in human muscle. In heterologous cells that constitutively express desmin, misfolded desmin molecules appear in aggregates.
MYOT (TTID)
Gene structure.
MYOT consists of ten exons. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. Five missense variants have been reported; all are in exon 2 [Hauser et al 2000, Hauser et al 2002, Selcen & Engel 2004]. See .
Table 4.
Selected MYOT Pathogenic Variants
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Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. Myotilin is a key Z-disk protein that interacts with α-actinin, filamin-C, and actin. It has 498 amino acid residues.
Abnormal gene product. Mutated myotilin is predicted to weaken the linkage of Z-disk filaments to thin filaments. Transgenic mice with the p.Thr57Ile pathogenic variant and muscle disease similar to LGMD1A have been described [Garvey et al 2006].
LDB3 (ZASP)
Gene structure.
LDB3 consists of 16 exons. It is alternatively spliced. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. Three missense variants have been reported [Selcen & Engel 2005]. See .
Table 5.
Selected LDB3 Pathogenic Variants
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Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Normal gene product. LIM domain-binding protein 3 (Zasp) is a key Z-disk protein that interacts with α-actinin and protein kinase C. It has 283 amino acid residues.
Abnormal gene product. Mutated LIM domain-binding protein 3 (Zasp) is predicted to weaken the linkage of Z-disk filaments to thin filaments.
BAG3
Gene structure.
BAG3 consists of four exons. No splice variants have been identified. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. The variant p.Pro209Leu has been reported [Selcen et al 2009]. See .
Table 6.
Selected BAG3 Pathogenic Variants
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Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. BAG family molecular chaperone regulator 3 (Bag3) is a co-chaperone for the Z-disk and has anti-apoptotic properties. It has 575 amino acid residues.
Abnormal gene product. Mutated Bag3 may alter the folding of Bag3 or may allosterically affect the binding properties of the canonical Bag3 domains.
DNAJB6
Gene structure.
DNAJB6 has published two alternatively spliced transcript variants that encode different protein isoforms. The longer transcript variant, NM_058246.3, has ten exons. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. Pathogenic variants have been reported [Harms et al 2012, Sarparanta et al 2012].
Normal gene product. The transcript NM_005494.2 encodes a protein isoform with 241 amino acid residues (NP_005485.1). DnaJ homolog subfamily B member 6 (DNAJB6) is a member of heat shock protein family with molecular chaperone function.
Abnormal gene product. In vitro studies demonstrated that the pathogenic missense variants increase the half-life of DNAJB6 and reduce its anti-aggregation effect [Sarparanta et al 2012].