Catalyzes the ATP-dependent ligation of glycine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP) (PubMed:17544401, PubMed:24898252, PubMed:28675565). Also produces diadenosine tetraphosphate (Ap4A), a universal pleiotropic signaling molecule needed for cell regulation pathways, by direct condensation of 2 ATPs. Thereby, may play a special role in Ap4A homeostasis (PubMed:19710017)

CytoplasmCell projection, axonSecretedSecreted, extracellular exosomeMitochondrion

Charcot-Marie-Tooth disease, axonal, type 2D

A dominant axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy.

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.

Inhibitor of actin polymerization

CytoplasmNucleus

Neuronopathy, distal hereditary motor, autosomal dominant 4

A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs.

Required for endoplasmic reticulum (ER) network formation, shaping and remodeling; it links ER tubules to the cytoskeleton. May also enhance the cell surface expression of odorant receptors (PubMed:20200447). May play a role in long-term axonal maintenance (PubMed:24478229)

MembraneMitochondrion membraneEndoplasmic reticulum

Spastic paraplegia 31, autosomal dominant

A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body.

Involved in the chaperone-assisted selective autophagy (CASA), a crucial process for protein quality control, particularly in mechanical strained cells and tissues such as muscle. Displays temperature-dependent chaperone activity

CytoplasmNucleus

Neuronopathy, distal hereditary motor, autosomal dominant 2

A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs.

Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of PDCD1/PD-1, thereby regulating T-cells-mediated immunity (PubMed:30487606). Required for anti-tumor activity of T-cells by promoting the degradation of PDCD1/PD-1; the PDCD1-mediated inhibitory pathway being exploited by tumors to attenuate anti-tumor immunity and facilitate tumor survival (PubMed:30487606). May indirec

Cytoplasm, cytosolNucleus

Neuronopathy, distal hereditary motor, autosomal dominant 6

A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs.

Small heat shock protein which functions as a molecular chaperone probably maintaining denatured proteins in a folding-competent state (PubMed:10383393, PubMed:20178975). Plays a role in stress resistance and actin organization (PubMed:19166925). Through its molecular chaperone activity may regulate numerous biological processes including the phosphorylation and the axonal transport of neurofilament proteins (PubMed:23728742)

CytoplasmNucleusCytoplasm, cytoskeleton, spindle

Charcot-Marie-Tooth disease, axonal, type 2F

A dominant axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. Onset of Charcot-Marie-Tooth disease type 2F is between 15 and 25 years with muscle weakness and atrophy usually beginning in feet and legs (peroneal distribution). Upper limb involvement occurs later.

Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane

Cytoplasm, cytoskeletonCytoplasm, cell cortex

Developmental and epileptic encephalopathy 5

A disorder characterized by seizures associated with hypsarrhythmia, profound intellectual disability with lack of visual attention and speech development, as well as spastic quadriplegia.

Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis (PubMed:19278620, PubMed:21533227, PubMed:30293840, PubMed:31708432). In association with LDAF1, defines the sites of LD formation in the ER (PubMed:31708432). Also required for growth and maturation of small nascent LDs into larger mature LDs (PubMed:27564575). Mediates the formation and/or stabilization of endoplasmic reticulum-lipid droplets (ER-LD) contacts

Endoplasmic reticulum membraneLipid droplet

Lipodystrophy, congenital generalized, 2

A form of congenital generalized lipodystrophy, a metabolic disorder characterized by a near complete absence of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. Inheritance is autosomal recessive.

Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity (PubMed:16293632, PubMed:18695040, PubMed:18826956, PubMed:22526352, PubMed:23136043, PubMed:29899501). Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification (PubMed:18695040, PubMed:18826956, PubMed:29899501). Also activated by heat, low pH, citrate and phorbol esters (PubMed:16293632, PubMed:18695040, PubMed:18826956, PubMed:20037586, PubMed:219

Cell membraneApical cell membraneCell junction, adherens junctionCell projection, ciliumEndoplasmic reticulum

Brachyolmia 3

A form of brachyolmia, a clinically and genetically heterogeneous skeletal dysplasia primarily affecting the spine and characterized by a short trunk, short stature, and platyspondyly. BCYM3 is an autosomal dominant form with severe scoliosis with or without kyphosis, and flattened irregular cervical vertebrae.

Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules (By similarity). Plays a key role in dynein-mediated retrograde transport of vesicles and organelles along microtubules by recruiting and tethering dynein to microtubules. Binds to both dynein and microtubules providing a link between specific cargos, microtubules and dynein. Essential for targeting dynein to microtubule plus ends, recruiting dynein to membranous cargos and en

CytoplasmCytoplasm, cytoskeletonCytoplasm, cytoskeleton, microtubule organizing center, centrosomeCytoplasm, cytoskeleton, microtubule organizing center, centrosome, centrioleCytoplasm, cytoskeleton, spindleNucleus envelopeCytoplasm, cell cortex

Neuronopathy, distal hereditary motor, autosomal dominant 14

A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs.

Involved in elastic and collagen fibers formation. It is required for EFEMP2 deposition into the extracellular matrix, and collagen network assembly and cross-linking via protein-lysine 6-oxidase/LOX activity (PubMed:36351433). May be responsible for anchoring smooth muscle cells to elastic fibers, and may be involved in the processes that regulate vessel assembly. Has cell adhesive capacity

Secreted, extracellular space, extracellular matrix

Neuronopathy, distal hereditary motor, autosomal dominant 10

A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular diseases caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. HMND10 is characterized by length-dependent motor neuropathy primarily affecting the lower limbs, and onset of distal muscle weakness and atrophy in early childhood resulting in walking difficulties and gait abnormalities. Some affected individuals have pyramidal signs, including hyperreflexia. More variable features may include mild intellectual disability, minor gyration defects on brain imaging, foot deformities, and connective tissue defects.

Catalyzes the attachment of tryptophan to tRNA(Trp) in a two-step reaction: tryptophan is first activated by ATP to form Trp-AMP and then transferred to the acceptor end of the tRNA(Trp) Has no angiostatic activity Possesses an angiostatic activity but has no aminoacylation activity (PubMed:11773625, PubMed:11773626, PubMed:14630953). Inhibits fluid shear stress-activated responses of endothelial cells (PubMed:14630953). Regulates ERK, Akt, and eNOS activation pathways that are associated with a

Cytoplasm

Neuronopathy, distal hereditary motor, autosomal dominant 9

A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. HMND9 is characterized by juvenile onset of slowly progressive distal muscle weakness and atrophy affecting both the lower and upper limbs.

High-affinity Na(+)-coupled choline transmembrane symporter (PubMed:11027560, PubMed:11068039, PubMed:12237312, PubMed:12969261, PubMed:17005849, PubMed:23132865, PubMed:23141292, PubMed:27569547). Functions as an electrogenic, voltage-dependent transporter with variable charge/choline stoichiometry (PubMed:17005849). Choline uptake and choline-induced current is also Cl(-)-dependent where Cl(-) is likely a regulatory ion rather than cotransported ion (PubMed:11068039, PubMed:12237312, PubMed:17

Presynaptic cell membraneCell projection, axonEarly endosome membraneCytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane

Neuronopathy, distal hereditary motor, autosomal dominant 7

A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. HMND7 is characterized by onset in the second decade of progressive distal muscle wasting and weakness affecting the upper and lower limbs and resulting in walking difficulties and hand grip. There is significant muscle atrophy of the hands and lower limbs. The disorder is associated with vocal cord paresis due to involvement of the tenth cranial nerve.