Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient.

Cell membraneCytoplasm, perinuclear regionCell membrane, sarcolemma, T-tubuleCell junction

Progressive familial heart block 1A

A cardiac bundle branch disorder characterized by progressive alteration of cardiac conduction through the His-Purkinje system, with a pattern of a right bundle-branch block and/or left anterior hemiblock occurring individually or together. It leads to complete atrio-ventricular block causing syncope and sudden death.

May function as an adapter in striated muscle to couple protein kinase C-mediated signaling via its LIM domains to the cytoskeleton

Cytoplasm, perinuclear regionCell projection, pseudopodiumCytoplasm, cytoskeletonCytoplasm, myofibril, sarcomere, Z line

Cardiomyopathy, dilated, 1C, with or without left ventricular non-compaction

A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. Cardiomyopathy dilated type 1C is associated with left ventricular non-compaction in some patients. Left ventricular non-compaction is characterized by numerous prominent trabeculations and deep intertrabecular recesses in hypertrophied and hypokinetic segments of the left ventricle.

Positive regulator of myogenesis. Acts as a cofactor for myogenic bHLH transcription factors such as MYOD1, and probably MYOG and MYF6. Enhances the DNA-binding activity of the MYOD1:TCF3 isoform E47 complex and may promote formation of a functional MYOD1:TCF3 isoform E47:MEF2A complex involved in myogenesis (By similarity). Plays a crucial and specific role in the organization of cytosolic structures in cardiomyocytes. Could play a role in mechanical stretch sensing. May be a scaffold protein t

NucleusCytoplasmCytoplasm, cytoskeletonCytoplasm, myofibril, sarcomere, Z lineCytoplasm, myofibril, sarcomere

Cardiomyopathy, dilated, 1M

A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.

May function as a molecular transmitter linking various signaling pathways to transcriptional regulation. Negatively regulates the transcriptional repressor E4F1 and may function in cell growth. Inhibits the transcriptional activity of FOXO1 and its apoptotic function by enhancing the interaction of FOXO1 with SIRT1 and FOXO1 deacetylation. Negatively regulates the calcineurin/NFAT signaling pathway in cardiomyocytes (PubMed:28717008)

CytoplasmNucleusCytoplasm, myofibril, sarcomere, Z line

Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity

Cardiomyopathy, familial hypertrophic, 7

A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.

Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity

Cardiomyopathy, familial hypertrophic, 2

A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.

Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q) (PubMed:10746566, PubMed:24781757). SDH also oxidizes malate to the non-canonical enol form of oxaloacetate, enol-oxaloacetate (By similarity). Enol-oxaloacetate, which is a potent inhibitor of the succinate dehydrogenase activity, is further isomerized into keto-oxaloacetate

Mitochondrion inner membrane

Mitochondrial complex II deficiency, nuclear type 1

A disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, cardiomyopathy. Some patients manifest Leigh syndrome or Kearns-Sayre syndrome. MC2DN1 inheritance is autosomal recessive.

RNA-binding protein that acts as a regulator of mRNA splicing of a subset of genes encoding key structural proteins involved in cardiac development, such as TTN (Titin), CACNA1C, CAMK2D or PDLIM5/ENH (PubMed:22466703, PubMed:24960161, PubMed:26604136, PubMed:27496873, PubMed:27531932, PubMed:29895960, PubMed:30948719, PubMed:32840935, PubMed:34732726, PubMed:35427468). Acts as a repressor of mRNA splicing: specifically binds the 5'UCUU-3' motif that is predominantly found within intronic sequenc

NucleusCytoplasm, Cytoplasmic ribonucleoprotein granule

Cardiomyopathy, dilated, 1DD

A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.

F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein

Cytoplasm, myofibril, sarcomere, Z line

Cardiomyopathy, familial hypertrophic, 23, with or without left ventricular non-compaction

A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.

Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and

CytoplasmCell membraneMitochondrionNucleus

Noonan syndrome 5

A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells.

Is an activator of the calcineurin/NFAT signaling pathway in cardiomyocytes, and is involved in myocardium morphogenesis, and regulation of myocardium mass and cardiac contractile function

Cytoplasm, myofibril, sarcomere, Z line

Cardiomyopathy, dilated, 1QQ

A form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD1QQ is an autosomal dominant form.

Essential for cardiac morphogenesis, particularly for the formation of the right ventricle and of the aortic arch arteries. Required for vascular development and regulation of angiogenesis, possibly through a VEGF signaling pathway. Also plays an important role in limb development, particularly in the establishment of anterior-posterior polarization, acting as an upstream regulator of sonic hedgehog (SHH) induction in the limb bud. Is involved in the development of branchial arches, which give r

Nucleus

Involved in the regulation of actin polymerization

Cell membrane

Cardiomyopathy, dilated, 2I

A form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD2I is an autosomal recessive, severe form characterized by onset in infancy or childhood.

Mediates nucleation of actin filaments and thereby promotes actin polymerization (PubMed:18403713, PubMed:25250574, PubMed:26370058, PubMed:26417072). Plays a role in the regulation of actin filament length (By similarity). Required for normal sarcomere organization in the heart, and for normal heart function (PubMed:18403713)

Cytoplasm, myofibril, sarcomereCytoplasm, myofibrilCytoplasm, myofibril, sarcomere, M lineCytoplasm, cytoskeleton

Cardiomyopathy, dilated, 2G

A form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD2G is an autosomal recessive form characterized by early-onset, severe cardiomyopathy that progresses rapidly to heart failure in the neonatal period without evidence of intervening hypertrophy.

A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion (PubMed:17559062, PubMed:38395410). Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. Required for proliferation and viability of embryonic stem cells in the blastocyst, thereby crucial for progression of post-implantation embryonic development (By similarity). Maintains pluripotency by regulating epithelial to mesenchymal transition/m

Cell membraneCell junction, desmosomeCytoplasm

Arrhythmogenic right ventricular dysplasia, familial, 10

A congenital heart disease characterized by infiltration of adipose and fibrous tissue into the right ventricle and loss of myocardial cells, resulting in ventricular and supraventricular arrhythmias.

ATPase required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum (PubMed:17382883). Recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol. This complex then targets to the endoplasmic reticulum by membrane-bound receptors GET1/WRB and CAMLG/GET2, where the tail-anchored protein is released for insertion. This process is regulated by ATP binding and hydrolysis. ATP binding drives the homodimer towards the closed dime

CytoplasmEndoplasmic reticulumNucleus, nucleolus

Cardiomyopathy, dilated, 2H

A form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD2H is an autosomal recessive form characterized by rapid progression and death in early infancy.

Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix

Cell membrane, sarcolemmaCytoplasm, cytoskeleton

Muscular dystrophy, limb-girdle, autosomal recessive 6

An autosomal recessive degenerative myopathy initially affecting the proximal limb girdle musculature. Muscle from patients shows a complete loss of delta-sarcoglycan as well as of the others components of the sarcoglycan complex.

Possible transcription factor. Specifically binds to the CT/GC-rich region of the interleukin-3 promoter and mediates tax transactivation of IL-3

Nucleus

Cardiomyopathy, dilated, 1OO

A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD1OO inheritance is autosomal dominant.

Catalyzes the transfer of a ribitol-phosphate from CDP-ribitol to the distal N-acetylgalactosamine of the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-3-N-acetylglucosamine-beta-4-(phosphate-6-)mannose), a carbohydrate structure present in alpha-dystroglycan (DAG1) (PubMed:26923585, PubMed:27194101, PubMed:29477842). This constitutes the first step in the formation of the ribitol 5-phosphate tandem repeat which links the phosphorylated O-mannosyl trisaccharide to the ligan

Golgi apparatus membraneCytoplasmNucleus

Muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A4

An autosomal recessive disorder characterized by congenital muscular dystrophy associated with cobblestone lissencephaly and other brain anomalies, eye malformations, profound intellectual disability, and death usually in the first years of life. Included diseases are the more severe Walker-Warburg syndrome and the slightly less severe muscle-eye-brain disease.

Catalyzes the second step in the biosynthesis of coenzyme A from vitamin B5, where cysteine is conjugated to 4'-phosphopantothenate to form 4-phosphopantothenoylcysteine (PubMed:11923312, PubMed:12906824, PubMed:29754768). Has a preference for ATP over CTP as a cosubstrate (PubMed:11923312)

Cardiomyopathy, dilated, 2C

A form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD2C is an autosomal recessive form with variable severity and age of onset ranging from 2 to 20 years. Death in infancy or early childhood may occur in severely affected children.

A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion (PubMed:25733715). Critical for cell-cell adhesion in early stage blastocysts and progression through proamniotic cavity formation (By similarity). Not required for preimplantation morphogenic process in blastocysts (By similarity). Required for keratin filament anchoring at the desmosome junction and subsequent organization of the keratin intermediate filament network within the cytoplas

Cell projection, axonCell junction, desmosomeCell membraneCytoplasmNucleus

Keratoderma, palmoplantar, striate 2

A dermatological disorder characterized by thickening of the skin on the palms (linear pattern) and the soles (island-like pattern) and flexor aspect of the fingers. Abnormalities of the nails, the teeth and the hair are rarely present.

Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:10206644, PubMed:10545183, PubMed:10593990, PubMed:10811883, PubMed:10899933, PubMed:12679784, PubMed:12740439, PubMed:15274632, PubMed:20460383, PubMed:25043039, PubMed:26280335, PubMed:28269784, PubMed:30598546, PubMed:30630874). Requires the presence of the other members of the

Endoplasmic reticulumEndoplasmic reticulum membraneGolgi apparatus membraneCytoplasmic granuleCell membraneCell projection, growth coneEarly endosomeEarly endosome membraneCell projection, neuron projectionCell projection, axonSynapse

Alzheimer disease 3

A familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death.

Membrane-binding protein that provides a structural bridge between the plasma membrane and the sarcoplasmic reticulum and is required for normal excitation-contraction coupling in cardiomyocytes (PubMed:20095964). Provides a structural foundation for functional cross-talk between the cell surface and intracellular Ca(2+) release channels by maintaining the 12-15 nm gap between the sarcolemma and the sarcoplasmic reticulum membranes in the cardiac dyads (By similarity). Necessary for proper intra

Cell membraneSarcoplasmic reticulum membraneEndoplasmic reticulum membraneNucleus

Cardiomyopathy, familial hypertrophic, 17

A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.

Transcription regulator that acts both as a histone methyltransferase or chromatin adapter, depending on the context (PubMed:12816872). In the cytoplasm, acts as a histone methyltransferase, which catalyzes monomethylation of 'Lys-9' of free histone H3 (H3K9me1) during translation (By similarity). Monomethylated histone H3 is then transported to the nucleus and incorporated into nucleosomes where SUV39H methyltransferases (SUV39H1 and SUV39H2) use it as a substrate to catalyze histone H3 'Lys-9'

NucleusChromosomeCytoplasm

Left ventricular non-compaction 8

A form of left ventricular non-compaction, a cardiomyopathy due to myocardial morphogenesis arrest and characterized by a hypertrophic left ventricle, a severely thickened 2-layered myocardium, numerous prominent trabeculations, deep intertrabecular recesses, and poor systolic function. Clinical manifestations are variable. Some affected individuals experience no symptoms at all, others develop heart failure. In some cases, left ventricular non-compaction is associated with other congenital heart anomalies. LVNC8 is an autosomal dominant condition.

Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane (PubMed:10080180, PubMed:10580070, PubMed:10587585, PubMed:10814726, PubMed:11799477, PubMed:12075506, PubMed:12927431, PubMed:15317753, PubMed:18551513, PubMed:18611980, PubMed:2188730, PubMed:22431096, PubMed:2344612, PubMed:23666920, PubMed:24741066, PubMed:31434876, PubMed:

Nucleus laminaNucleus envelopeNucleus, nucleoplasmNucleus matrixNucleus speckle

Emery-Dreifuss muscular dystrophy 2, autosomal dominant

A form of Emery-Dreifuss muscular dystrophy, a degenerative myopathy characterized by weakness and atrophy of muscle without involvement of the nervous system, early contractures of the elbows, Achilles tendons and spine, and cardiomyopathy associated with cardiac conduction defects.

Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands. In vitro it binds MHC, F-actin and native thin filaments, and modifies the activity of actin-activated myosin ATPase. It may modulate muscle contraction or may play a more structural role

Cardiomyopathy, familial hypertrophic, 4

A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.

Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity

Cardiomyopathy, familial hypertrophic, 7

A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.

Component of the sarcomere that tethers together nebulin (skeletal muscle) and nebulette (cardiac muscle) to alpha-actinin, at the Z lines

CytoplasmNucleusCytoplasm, myofibril, sarcomereCytoplasm, myofibril, sarcomere, Z line

Congenital myopathy 24

An autosomal recessive muscular disorder characterized by slowly progressive muscle weakness and atrophy, mainly affecting the lower limbs and neck. Some patients may have mild cardiac or respiratory involvement, but they do not have respiratory failure. Muscle biopsy shows nemaline bodies.

Component of the transcription factor SL1/TIF-IB complex, which is involved in the assembly of the PIC (pre-initiation complex) during RNA polymerase I-dependent transcription. The rate of PIC formation probably is primarily dependent on the rate of association of SL1/TIF-IB with the rDNA promoter. SL1/TIF-IB is involved in stabilization of nucleolar transcription factor 1/UBTF on rDNA. Formation of SL1/TIF-IB excludes the association of TBP with TFIID subunits

Nucleus, nucleolus

Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells

Cytoplasm, cytoskeleton

Cardiomyopathy, dilated, 1R

A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.

May contribute to the transparency and refractive index of the lens. Has chaperone-like activity, preventing aggregation of various proteins under a wide range of stress conditions. In lens epithelial cells, stabilizes the ATP6V1A protein, preventing its degradation by the proteasome (By similarity)

CytoplasmNucleusSecretedLysosome

Myopathy, myofibrillar, 2A, adult-onset

A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM2A is an autosomal dominant form characterized by weakness of the proximal and distal limb muscles, weakness of the neck, velopharynx and trunk muscles, respiratory insufficiency, hypertrophic cardiomyopathy, and cataract.

Heart- and skeletal muscle-specific component of the ribosome, which regulates muscle function. Component of the large ribosomal subunit in striated muscle cells: replaces the RPL3 paralog in the ribosome in these cells. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. Inhibits myotube growth and muscle function

Cardiomyopathy, dilated, 2D

A form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD2D is an autosomal recessive, severe form with neonatal onset.

May play an important role in endothelial cell activation. May act as a nuclear transcription factor that negatively regulates the expression of cardiac genes. Induction seems to be correlated with apoptotic cell death in hepatoma cells

Nucleus

May be involved in the structural organization of the nucleus and in the post-mitotic nuclear assembly. Plays an important role, together with LMNA, in the nuclear anchorage of RB1 TP and TP5 may play a role in T-cell development and function. TP5 is an immunomodulating pentapeptide

NucleusChromosome

Co-chaperone for HSP/HSP70 proteins. It functions as a nucleotide-exchange factor promoting the release of ADP from HSP70, thereby activating HSP70-mediated protein refolding (PubMed:20223214). Has an essential role in maintaining proteostasis at junctional membrane complexes (JMC), where it may function as a scaffold between the HSPA8 chaperone and JMC proteins enabling correct, HSPA8-dependent JMC protein folding (By similarity). Inhibits both auto-ubiquitination of PRKN and ubiquitination of

Cardiomyopathy, dilated, 2F

A form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD2F is an autosomal recessive, early-onset form.

Reversibly inhibits the activity of ATP2A2/SERCA2 in cardiac sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+) (PubMed:28890335). Binds preferentially to the ATP-bound E1 conformational form of ATP2A2 which predominates at low Ca(2+) concentrations during the diastolic phase of the cardiac cycle (By similarity). Inhibits ATP2A2 Ca(2+) affinity by disrupting its allosteric activation by ATP (By similarity). Modulates the contractility of the heart muscle in respo

Endoplasmic reticulum membraneSarcoplasmic reticulum membraneMitochondrion membraneMembrane

Cardiomyopathy, dilated, 1P

A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.

Muscle assembly regulating factor. Mediates the antiparallel assembly of titin (TTN) molecules at the sarcomeric Z-disk

Cytoplasm, myofibril, sarcomere

Cardiomyopathy, familial hypertrophic, 25

A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.

Component of some chromatin complex recruited to chromatin sites methylated 'Lys-4' of histone H3 (H3K4me), with a preference for trimethylated form (H3K4me3)

Nucleus

Cardiomyopathy, dilated, 2B

A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.

Catalyzes CTP-mediated phosphorylation of dolichol, the terminal step in de novo dolichyl monophosphate (Dol-P) biosynthesis (PubMed:12213788, PubMed:16923818, PubMed:17273964, PubMed:22242004). Dol-P is a lipid carrier essential for the synthesis of N-linked and O-linked oligosaccharides and for GPI anchors (PubMed:12213788)

Endoplasmic reticulum membrane

Congenital disorder of glycosylation 1M

A form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. CDG1M is a very severe disease with death occurring in early life.

Key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The size and extensibility of the cross-links are the main determinants of sarcomere extensibility properties of muscle. In non-muscle cells, seems to play a role in chromosome condensation and chromosome segregation during mitosis. Might link the lamina network to ch

CytoplasmNucleus

Myopathy, myofibrillar, 9, with early respiratory failure

An autosomal dominant myopathy characterized by adulthood onset of weakness in proximal, distal, axial and respiratory muscles. Pelvic girdle weakness, foot drop and neck weakness are the main symptoms at onset, but ultimately the weakness usually involves the proximal compartment of both upper and lower limbs. Additional features include variable degrees of Achilles tendon contractures, spinal rigidity and muscle hypertrophy. Respiratory involvement often leads to requirement for non-invasive ventilation support.

Actin filament (F-actin)-binding protein involved in cell-matrix adhesion and cell-cell adhesion. Regulates cell-surface E-cadherin expression and potentiates mechanosensing by the E-cadherin complex. May also play important roles in cell morphology and locomotion

Cell membraneCell junction, adherens junctionCell junction, focal adhesionCytoplasm, cytoskeletonCell membrane, sarcolemmaCell projection, podosomeCytoplasm, perinuclear region

Cardiomyopathy, dilated, 1W

A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.

Involved in regulating cell migration through association with the actin cytoskeleton. Has an essential role in the maintenance of Z line and sarcomere integrity

Cytoplasm, cytoskeletonCell junction, adherens junctionCytoplasm, myofibril, sarcomere, Z line

Cardiomyopathy, dilated, 1CC

An autosomal dominant form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.

Anchors the extracellular matrix to the cytoskeleton via F-actin. Ligand for dystroglycan. Component of the dystrophin-associated glycoprotein complex which accumulates at the neuromuscular junction (NMJ) and at a variety of synapses in the peripheral and central nervous systems and has a structural function in stabilizing the sarcolemma. Also implicated in signaling events and synaptic transmission

Cell membrane, sarcolemmaCytoplasm, cytoskeletonPostsynaptic cell membrane

Duchenne muscular dystrophy

Most common form of muscular dystrophy; a sex-linked recessive disorder. It typically presents in boys aged 3 to 7 year as proximal muscle weakness causing waddling gait, toe-walking, lordosis, frequent falls, and difficulty in standing up and climbing up stairs. The pelvic girdle is affected first, then the shoulder girdle. Progression is steady and most patients are confined to a wheelchair by age of 10 or 12. Flexion contractures and scoliosis ultimately occur. About 50% of patients have a lower IQ than their genetic expectations would suggest. There is no treatment.

Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components

Secreted, extracellular space, extracellular matrix, basement membraneSecreted

Cardiomyopathy, dilated, 1JJ

A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.

Muscle-specific type III intermediate filament essential for proper muscular structure and function. Plays a crucial role in maintaining the structure of sarcomeres, inter-connecting the Z-disks and forming the myofibrils, linking them not only to the sarcolemmal cytoskeleton, but also to the nucleus and mitochondria, thus providing strength for the muscle fiber during activity (PubMed:25358400). In adult striated muscle they form a fibrous network connecting myofibrils to each other and to the

Cytoplasm, myofibril, sarcomere, Z lineCytoplasmCell membrane, sarcolemmaNucleusCell tipNucleus envelope

Myopathy, myofibrillar, 1

A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM1 is characterized by skeletal muscle weakness associated with cardiac conduction blocks, arrhythmias, restrictive heart failure, and accumulation of desmin-reactive deposits in cardiac and skeletal muscle cells.

Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:10497236, PubMed:10652302, PubMed:16752394, PubMed:27293189, PubMed:36272978). Selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular amyloid beta that contains longer amyloid beta (PubMed:27293189). The holoprotein func

Endoplasmic reticulum membraneGolgi apparatus membraneLate endosome membraneLysosome membrane

Alzheimer disease 4

A familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death.

Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with KCNJ11. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation (PubMed:9831708). Can form a sulfonylurea-sensitive but ATP-insensitive potassium channel with KCNJ8 (By similarity)

Membrane

Cardiomyopathy, dilated, 1O

A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.

Co-chaperone and adapter protein that connects different classes of molecular chaperones including heat shock proteins 70 (HSP70s), e.g. HSPA1A/HSP70 or HSPA8/HSC70, and small heat shock proteins (sHSPs), e.g. HSPB8 (PubMed:27884606, PubMed:30559338). Acts as a nucleotide-exchange factor (NEF) promoting the release of ADP from HSP70s, thereby triggering client protein release (PubMed:27884606, PubMed:30559338). Nucleotide release is mediated via BAG3 binding to the nucleotide-binding domain (NBD

NucleusCytoplasm

Myopathy, myofibrillar, 6

A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM6 is characterized by early-onset of severe, progressive, diffuse muscle weakness associated with cardiomyopathy, severe respiratory insufficiency during adolescence, and a rigid spine in some patients.

Involved in the control of reactive oxygen species levels and the regulation of mitochondrial redox homeostasis (PubMed:24601690). Maintains thioredoxin in a reduced state. May play a role in redox-regulated cell signaling

Mitochondrion

Glucocorticoid deficiency 5

A form of glucocorticoid deficiency, a rare autosomal recessive disorder characterized by resistance to ACTH action on the adrenal cortex, adrenal insufficiency and an inability of the adrenal cortex to produce cortisol. It usually presents in the neonatal period or in early childhood with episodes of hypoglycemia and other symptoms related to cortisol deficiency, including failure to thrive, recurrent illnesses or infections, convulsions, and shock. In a small number of patients hypoglycemia can be sufficiently severe and persistent that it leads to serious long-term neurological damage or death. The diagnosis is readily confirmed with a low plasma cortisol measurement in the presence of an elevated ACTH level, and normal aldosterone and plasma renin measurements.

Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction. Forms regular bipolar thick filaments that, together with actin thin filaments, constitute the fundamental contractile unit of skeletal and cardiac muscle

Cytoplasm, myofibrilCytoplasm, myofibril, sarcomere

Cardiomyopathy, familial hypertrophic, 1

A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.

Binds to actin filaments in muscle and non-muscle cells (PubMed:23170982). Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction (PubMed:23170982). Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments

Cytoplasm, cytoskeleton

Cardiomyopathy, familial hypertrophic, 3

A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.

Acyltransferase required to remodel newly synthesized phospholipid cardiolipin (1',3'-bis-[1,2-diacyl-sn-glycero-3-phospho]-glycerol or CL), a key component of the mitochondrial inner membrane, with tissue specific acyl chains necessary for adequate mitochondrial function (PubMed:12930833, PubMed:19164547, PubMed:19700766, PubMed:26908608, PubMed:33096711). Its role in cellular physiology is to improve mitochondrial performance (PubMed:32234310). CL is critical for the coassembly of lipids and p

Mitochondrion outer membraneMitochondrion inner membraneMitochondrion membraneCytoplasm

Barth syndrome

An X-linked disease characterized by dilated cardiomyopathy with endocardial fibroelastosis, a predominantly proximal skeletal myopathy, growth retardation, neutropenia, and organic aciduria, particularly excess of 3-methylglutaconic acid. Additional features include hypertrophic cardiomyopathy, isolated left ventricular non-compaction, ventricular arrhythmia, motor delay, poor appetite, fatigue and exercise intolerance, hypoglycemia, lactic acidosis, hyperammonemia, and dramatic late catch-up growth after growth delay throughout childhood.

Muscle contraction

Cytoplasm, myofibril

Atrial septal defect 3

A congenital heart malformation characterized by incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria.