DYSFERLIN BACKGROUND

Dysferlin Facts

DYSFERLIN BACKGROUND

Dysferlin Facts

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Dysferlin Facts

This is a catalog of basic information pertaining to dysferlin in an easy-to-navigate question-based format. Click on any of the facts below to learn more.

Dysferlin Gene

The human Dysferlin gene is located on chromosome 2, position 2p13.3-p13.1

The coding sequence of Dysferlin is comprised of 55 exons. The first two splice variants of Dysferlin that were described, “original” and “variant-1” are 6907bp and 6543bp in length respectively.

The DYSF gene has four alternatively spliced exons: exon 1/1A, exon 5A, exon 17 and exon 40A. Variations in the inclusion of these exons results in 15 different dysferlin transcripts that have been detected in various tissues.

For more information go to Pramono et al 2009 and/or the Uniprot entry for the Dysferlin gene.

Dysferlin Protein

The full length dysferlin protein is 230kD with some slight variations between isoforms.

The major structural domains for dysferlin are C2 domains (7) a DysF domain (1), a Fer domains (2) and a single pass transmembrane domain (1).

  • The transmembrane domain anchors dysferlin to lipid membranes by C-terminus.
  • The C2 domains are known to have lipid binding activity that can be altered by calcium.
  • The functions of the DysF and Fer domains are not known.
Dysferlin Expression

Dysferlin can be clearly visualized at the muscle sarcolemma by immunostaining of normal muscle, however this represents a minority fraction of the total dysferlin in a muscle, with most of the dysferlin associating with internal reticular membranes consistent with its presence in T-tubules (Ampong et al., Acta Myologica 24: 134-144; Klinge et al., FASEB J 21: 1768-1776). The surface localization of dysferlin is absent or markedly reduced in patients suffering from MM/LGMD2B (Anderson et al., Human Molecular Genetics 8 (5): 855-861; Glover and Brown, Traffic 8: 785-794; Piccolo et al., Ann Neurol 48: 902-912). Dysferlin localization in C2C12 myotubes is largely intracellular and gives a reticular staining pattern. It is widely believed that cytoplasmic vesicles also harbor Dysferlin, though a direct localization to the vesicular compartment has not been demonstrated (Piccolo et al., Ann Neurol 48: 902-912).

Dysferlin protein in human fetal muscle tissue can be detected at embryonic weeks 5-6, a stage when limbs begin to show regional differentiation (Anderson et al., Human Molecular Genetics 8 (5): 855-861). Dysferlin shows differential expression and subcellular distribution during early myogenesis. Data from primary human muscle cultures indicates that the level of dysferlin RNA progressively increases as myoblasts differentiate into myotubes (deLuna et al., J of Neuropath Exp Neuro 63 (10): 1104-1113). Consistent with this transcriptional pattern, C2C12 cultures show that Dysferlin protein expression begins at later stages of myoblast fusion.

The highest expression of Dysferlin protein is found in skeletal and cardiac muscle, and kidneys. Dysferlin expression has been reported in satellite cells (SCs) and certain immune cells like monocytes and macrophages. A shorter transcript of 4kb is detectable in the brain and faint, lower molecular weight bands can be detected in the brain stem, spinal cord and sciatic nerve (Glover and Brown, Traffic 8: 785-794; deLuna et al., J of Neuropath Exp Neuro 63 (10): 1104-1113; Anderson et al., Human Molecular Genetics 8 (5): 855-861). Dysferlin is also expressed in human placental microvillus syncytiotrophoblasts (Vandre et al., Biol Reprod 77: 533-542). Dysferlin positive staining is also observed in stomach, lung, liver and spleen tissue from rats (Anderson et al., Human Molecular Genetics 8 (5): 855-861).