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FLASH GENE

Symbol

DYSF

contributors: mct/npt/pgu - updated : 23-02-2016

HGNC name	dysferlin, limb girdle muscular dystrophy 2B (autosomal recessive)
HGNC id	3097

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	DMAT myopathy, distal with anterior tibial onset LGMD2B limb girdle muscular dystrophy 2B MMD1 Miyoshi myopathy 1
Location	2p13.2      Physical location : 71.680.752 - 71.913.892
Synonym name	dystrophy-associated fer-1-like 1
	Fer-1-like protein 1
	dystrophy-associated fer-1-like protein
Synonym symbol(s)	FER1L1, LGMD2B, FLJ00175, FLJ90168

DNA

TYPE	functioning gene
STRUCTURE	233.14 kb     55 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	cytosine-phosphate-guanine/HTF
	Binding site   silencer

MAPPING

cloned

Y

linked

N

status

confirmed

Map	see LGMD2B

RNA

TRANSCRIPTS	type	messenger

text	fourteen dysferlin transcripts (PMID: 19221801) alternative splicing involving exons 5a and 40a, in addition to previously reported alternative splicing of exon 17 (PMID: 19221801)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001130987 55 - 6772 NP_001124459 - 2119 - 2009 19221801 NM_001130455 56 - 6682 NP_001123927 230 2081 skeletal muscle, heart, placenta, brain, spleen, kidney, intestine, and lung tissues 2009 19221801 retains phylogenic conservancy and shows similar expression pattern as the currently known human dysferlin NM_003494 55 - 6914 NP_003485 - 2080 - 2009 19221801 NM_001130986 - - 6616 NP_001124458 - 2067 - 2009 19221801 NM_001130985 - - 6709 NP_001124457 - 2098 - 2009 19221801 NM_001130984 - - 6679 NP_001124456 - 2088 - 2009 19221801 NM_001130983 - - 6721 NP_001124455 - 2102 - 2009 19221801 NM_001130982 - - 6775 NP_001124454 - 2112 - 2009 19221801 NM_001130981 56 - 7004 NP_001124453 - 2118 - 2009 19221801 NM_001130980 55 - 6941 NP_001124452 - 2097 - 2009 19221801 NM_001130979 56 - 6983 NP_001124451 - 2111 - 2009 19221801 NM_001130978 56 - 6953 NP_001124450 - 2101 - 2009 19221801 NM_001130977 55 - 6911 NP_001124449 237 2087 - 2009 19221801 NM_001130976 54 - 6848 NP_001124448 - 2066 - 2009 19221801

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular vessel       highly Homo sapiens Adult Lymphoid/Immune spleen       highly Nervous brain       moderately Reproductive female system placenta     highly Urinary kidney       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal     Homo sapiens Adult

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic monocyte Homo sapiens Adult Cardiovascular endothelial cell Homo sapiens Adult

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

pregnancy

Text	placenta, in mononuclear cytotrophoblasts and the syncytiotrophoblast

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	seven calcium-dependent C2 binding domains, which are required to promote fusion of intracellular membrane vesicles
	a C2A domain binding to AHNAK
	several nuclear membrane targeting sequences, a single transmembrane segment
	two highly conserved DYSF domains, namely DYSF N in the N-terminus and DYSF C in the C-terminus, with unknown function
	a short C terminal extracellular tail, that is an apparent binding site for affixin

mono polymer

dimer

HOMOLOGY

interspecies

homolog to C.elegans spermatogenesis factor fer-1

Homologene

FAMILY

dysferlin family

CATEGORY

structural protein

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,cytosolic,vesicle
text	in normal skeletal muscle, dysferlin and AHNAK colocalize at the sarcolemmal membrane and T-tubules
	abundant dysferlin expression in the Golgi apparatus, around the perinuclear region and to a lesser extent in the nucleus of endothelial cells

basic FUNCTION	involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events
	involved in membrane regeneration and repair (first member of the membrane repair machinery in skeletal muscle)
	implicated in calcium-dependent membrane repair
	participates in the recruitment and stabilization of AHNAK to the sarcolemma
	involved in efficient and active membrane repair system to overcome the rigours of frequent contraction of the muscles
	is necessary for correct T-tubule formation, and dysferlin-deficient skeletal muscle is characterized by abnormally configured T-tubules
	role for the muscle repair protein dysferlin in endothelial cell adhesion and angiogenesis
	ferlins are calcium-sensing proteins and are candidate mediators of vesicle-plasma membrane fusion during myoblast fusion
	membrane-anchored protein known to facilitate membrane repair in skeletal muscles following mechanical injury
	not only mediates membrane repair but also trafficking of client proteins, ultimately, help bridging dysferlinopathies to aberrant membrane signaling
	indirectly regulates the membrane expression of proteins by trafficking the lipid patches/vesicles that contain membrane proteins, rather than binding directly the cargo proteins
	multi-C2 domain transmembrane protein involved in skeletal muscle membrane repair, but also in myogenesis, cellular adhesion and intercellular calcium signaling

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	CAPN3/DYSF
	DYSF dimerization is mediated by its transmembrane domain and by multiple C2 domains
	RIPOR2 is an essential component of the HDAC6-dysferlin complex

INTERACTION

DNA

RNA

small molecule

protein	CAPN3
	CAV3 (putative low affinity process)and CAV1 (caveolins are essential for dysferlin association with the plasma membrane)
	interacting with other dysferlin molecules and annexins A1 and A2 at the sarcolemma
	interacting with PARVB
	interacts with alpha-tubulin and microtubules in muscle cells
	ferlins and EHBP1 may compete for EHD binding to regulate the complex process of exit from the endocytic recycling compartment, translocation to the plasma membrane, and reorganization of the actin cytoskeleton to facilitate the fusion of exocytosed vesicles to the membrane
	HDAC6 is a novel dysferlin-binding partner(DYSF prevents HDAC6 from deacetylating alpha-tubulin by physically binding to both the enzyme, via its C2D domain, and to the substrate, alpha-tubulin, via its C2A and C2B domains)
	DYSF interacts with CASQ1, MYOM2 and dynein in human skeletal muscle

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

DMAT , LGMD2B , MMD1

related resource

Limb-Girdle Muscular Dystrophy ,type 2B

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neuromuscular myopathy   enhancement of the neutrophil response is a potential therapeutic avenue in the dysferlinopathies

ANIMAL & CELL MODELS

	deleted in SJL mice
	overexpression of dysferlin in mice resulted in a striking phenotype of kyphosis, irregular gait, and reduced muscle mass and strength