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FLASH GENE

Symbol

DMD

contributors: mct/pgu - updated : 04-03-2015

HGNC name	dystrophin
HGNC id	2928

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	2220.38 kb     79 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	alternative promoter
	Binding site   enhancer
text structure	alternative promoters of the muscle, brain, cerebellar Purkinje enhancer : dystrophin muscle enhancer 1 (DME1)
	muscle-specific enhancer 2 (DME2), within intron1 (activity may be restricted to later stages of cardiac muscle development )

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

text	contains at least seven internal promoters that produce different tissue-specific dystrophins, named according with their molecular weights as Dp427, Dp260, Dp116, Dp140, and Dp71

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004006 79 - 13993 NP_003997 427 3685 - 1992 1307251 also called DYS, DP427m specific promoter, unique N terminus large, rod-like cytoskeletal protein at found at the inner surface of muscle fibers. NM_004011 51 initiation site 9771 NP_004002 260 2344 retina outer plexiform layer 1992 1307251 also called DP260-1 promoter/exon 1 in intron 29, exons 30-79 impairment related to dystrophin isoform Dp260 leads to red-green color defect NM_004013 36 splicing 7410 NP_004004 140 1225 central nervous system, kidney 1992 1307251 also called DP140 may be involved in cognitive development, promoter/exon 1 in intron 44, exons 45-79 strong association between the risk of cognitive disability and deltion of this isoform (PMID: 20098710) NM_004014 25 splicing 5623 NP_004005 116 956 peripheral nerve 1992 1307251 also called DP116 anchored with utrophin in a sarcoglycan complex, promoter/exon 1 in intron 55, exons 56-79 NM_004019 - initiation site 1571 NP_004010 40 340 - 1988 3180845 also called DP40 same start site than DP71, exons 63-710 NM_004017 17 splicing initiation site 4584 NP_004008 71 604 microsomes, nuclear variant 1992 1307251 also called DP71a/DP71d or Dp71a start site for a new coding sequence, exons 63-79, lacking exon 71 associates with the nuclear matrix dynamic component of nuclear matrix that might participate in the nuclear modeling occurring during neuronal differentiation NM_004023 33 splicing initiation site 7048 NP_004014 140 1133 - 1992 1307251 also called DP140bc promoter/exon 1 in intron 44, exons 45-79, start site in exon 51, lacking exons 71-4 and 78 NM_004016 17 splicing initiation site 4591 NP_004007 71 635 mitochondria, cytoplasmic variant 1992 1307251 also called DP71b/DP71f or Dp71b start site for a new coding sequence, exons 63-79, lacking exon 78 NM_004010 79 initiation site 14082 NP_004001 - 3562 - 1992 1307251 also called DP427p2 insertion of 82 nucleotides after exon 1 NM_000109 82 initiation site 14069 NP_000100 - 3677 neurons, cortex, hippocampus 1992 1307251 also called DP427c promoter upstream DP427m, unique N terminus NM_004021 35 - 7378 NP_004012 140 1243 - 1992 1307251 also called DP140b promoter/exon 1 in intron 44, exons 45-79, start site exon 51, lacking exon 78 NM_004012 51 initiation site 9914 NP_004003 260 2341 - 1992 1307251 also called DP260-2 promoter/exon 1 in intron 29, exons 30-79 NM_004022 34 splicing initiation site 7339 NP_004013 140 1230 - 1992 1307251 also called DP140ab promoter/exon 1 in intron 44, exons 45-79, start site exon 51, lacking exons 71 and 78 NM_004020 33 splicing initiation site 7050 NP_004011 140 1105 - 1992 1307251 also called DP140c promoter/exon 1 in intron 44, exons 45-79, start site exon 51, lacking exon 71-74 NM_004015 18 - 4623 NP_004006 71 617 most abundant dystrophin product in the brain 2009 19602481 also called DP71 start site for a novel coding sequence, exons 63-79 including exons 71 and 78, most abundant product has its promoter region and specific first exon between exons 62 and 63 (7 kb upstream to exon 63) required for development of cognitive functions and provide insights into the understanding of molecular mechanisms underlying cognitive impairment associated with DMD and BMD phenotype down-regulation of the Dp71 promoter activity down-regulated during myogenesis, in differentiated cells, and efficient promoter activity was restored in differentiated muscle cells by exogenous expression of Sp1 and Sp3 NM_004018 15 - 4552 NP_004009 11 622 microsomes 1992 1307251 also called DP71ab start site for a new coding sequence, exons 63-79 lacking exon 71, 78

EXPRESSION

Type	ubiquitous

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 heart         Hearing/Equilibrium ear inner cochlea   highly Nervous brain           nerve       highly Visual eye retina

tissue

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

cells

System Cell Pubmed Species Stage Rna symbol Visual rod photoreceptor

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal part of dystrophin is reported as a globular actin binding domain 1 (N-ABD), and WW domain
	one actin-binding domain
	a central rod domain with 24 weakly repeating units of 110 AAs similar to the coiled-coil repeats of spectrin, and disrupted by
	four potential hinges that may ensure flexibility (critical role for the rod domain in different aspects of dystrophin function, in particular a reduced stability of the R23 repeat)
	two calponin homology (CH) domains within the actin-binding domain
	C terminal ZZ type zinc binding domain required for the binding of dystrophin and utrophin to beta dystroglycan, a cysteine-rich zinc-finger domain near the dystrophin C-terminus, implicated in forming a stable interaction between dystrophin and beta-dystroglycan

secondary structure

homologous sequence motifs have been proposed to form domains with a triple-helical bundle-type structure

HOMOLOGY

interspecies

homolog to murine Dmd

Homologene

FAMILY

CATEGORY

structural protein

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,cytoplasm,cytoskeleton
	intracellular,nucleus,nucleoplasm
text	inner surface of striated muscles, beneath the sarcolemma

basic FUNCTION	involved in muscle development and vision (anchoring the cytoskeleton to the plasma membrane)
	stabilizes the cell membrane of muscle cells against the mechanical forces associated with muscle contraction and stretch
	muscle scaffolding protein that establishes a structural link between the cytoskeleton and the extracellular matrix
	with utrophin have distinct effects on the structural dynamics of actin
	in addition to its protective role, may act as a signaling molecule in cell signaling pathways such as muscle cell growth, cytoskeleton organization, muscle homeostasis, and atrophy/hypertrophy
	recruits neuronal nitric oxide synthase (NOS1) to the sarcolemma, but not UTRN
	acts as a link between the sarcolemma transmembrane glycoprotein complex and actin fibers, protecting actin filaments against depolymerization
	DMD and UTRN are highly similar proteins that both link cortical actin filaments with a complex of sarcolemmal glycoproteins, yet localize to different subcellular domains within normal muscle cells
	DMD binds microtubules with high affinity and pauses microtubule polymerization, whereas utrophin has no activity in either assay
	is a tumor suppressor and likely anti-metastatic factor

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

sensory transduction/vision

a component

part of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton (F-actin) and the extra-cellular matrix

INTERACTION

DNA

RNA

small molecule

protein	binding ANK2, ANK3 (require ANK3 for retention at costameres but not delivery to the sarcolemma)
	associating with the dystroglycan complex
	interacting with SYNM, an important IF protein in muscle cells that helps fortify the linkage between the peripheral layer of cellular myofibrils and the costameric regions located along the sarcolemma
	with UTRN, bind to actin with similar affinities, and both stabilize actin filaments against depolymerization, but dystrophin and utrophin differ in their effects on the extent of lateral association with actin and in the ionic strength dependence of actin binding
	ANK2 binds to dystrophin, DCTN4, and microtubules and is required for sarcolemmal association of these proteins as well as dystroglycan
	UTRN and DMD interact with actin through their N-terminal actin-binding domain (N-ABD)
	SSPN is a necessary component of DMD and UTRN function

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

BMD , CMD3B , DMD , OED , DELXP21

related resource

Becker

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional   deletion     disruption to the amino terminus in end stage cardiomyopathy constitutional     --low   lack of dystrophin leads to a general dysregulation of vesicle trafficking

Susceptibility

to viral (enterovirus) heart disease and increased risk of cardiomyopathy

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neuromuscular myopathy degenerative suramin, a transforming growth factor-beta 1 (TGF-beta1) blocker, might be a useful therapeutic alternative for the treatment of dystrophinopathies (DMD and other myopathy)

ANIMAL & CELL MODELS

	increased levels of matrix metalloproteinase-9 (Mmp-9) protein causes myopathy in dystrophin-deficient mdx mice
	suramin decreased creatine kinase in mdx mice and attenuated fibrosis in all muscles studied, except for cardiac muscle
	severe muscle phenotype observed in mdx/mTRG2 animals is caused by defects in muscle stem cells function (MUSC), demonstrating that progressive loss of MUSC reserve plays a major role in determining the severity of the dystrophic phenotype
	mice lacking utrophin and dystrophin (mdx/utrn -/-) are severely affected and die prematurely
	altered acetylcholine release in the hippocampus of dystrophin-deficient mice