Iron-sulfur cluster assembly enzyme ISCU, mitochondrial is a protein that in humans is encoded by the ''ISCU''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ...

. It encodes an iron-sulfur (Fe-S) cluster

scaffold protein In biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signalling pathway, tethering them i ...

involved in 2Fe-2S.html" ;"title="2Fe-2S_cluster.html" ;"title="nowiki/>2Fe-2S cluster">2Fe-2S">2Fe-2S_cluster.html" ;"title="nowiki/>2Fe-2S cluster">2Fe-2Sand [4Fe-4S] cluster synthesis and maturation. A deficiency of ISCU is associated with a mitochondrial myopathy with lifelong

exercise intolerance Exercise intolerance is a condition of inability or decreased ability to perform physical exercise at the normally expected level or duration for people of that age, size, sex, and muscle mass. It also includes experiences of unusually severe post ...

where only minor exertion causes

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...

shortness of breath Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...

muscle weakness Muscle weakness is a lack of muscle strength. Its causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, includi ...

and

myalgia Myalgia (also called muscle pain and muscle ache in layman's terms) is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another li ...

. Updated 2011 Sep 1

Structure

''ISCU'' is located on the

q arm In genetics, a locus (plural loci) is a specific, fixed position on a chromosome where a particular gene or genetic marker is located. Each chromosome carries many genes, with each gene occupying a different position or locus; in humans, the to ...

of chromosome 12 in position 23.3 and has 8

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

s. ISCU, the protein encoded by this gene, is a member of the NifU family. It is an iron-sulfur

transferase A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of di ...

that contains binding sites for 2Fe-2S.html" ;"title="2Fe-2S_cluster.html" ;"title="nowiki/>2Fe-2S cluster">2Fe-2S">2Fe-2S_cluster.html" ;"title="nowiki/>2Fe-2S cluster">2Fe-2Sand [4Fe-4S] clusters. ISCU contains a transit peptide, 4 Beta sheet, beta strands, 4 alpha helixes, and 4 turns. Alternative splicing results in transcript variants encoding different

protein isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

s that localize either to the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochond ...

or to the

mitochondrion A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used t ...

. A

pseudogene Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Most arise as superfluous copies of functional genes, either directly by DNA duplication or indirectly by reverse transcription of an mRNA transcript. Pseudogenes are ...

of this gene is present on

chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ...

Function

''ISCU'' encodes a component of the iron-sulfur (Fe-S) cluster scaffold responsible for the synthesis and maturation of 2Fe-2S.html" ;"title="2Fe-2S_cluster.html" ;"title="nowiki/>2Fe-2S cluster">2Fe-2S">2Fe-2S_cluster.html" ;"title="nowiki/>2Fe-2S cluster">2Fe-2Sand [4Fe-4S] clusters. Fe-S clusters are Cofactor (biochemistry), cofactors that play a role in the function of a diverse set of enzymes, including those that regulate metabolism, Human iron metabolism, iron homeostasis, and oxidative stress response. In one process, the Fe-2Scluster transiently assembles on ISCU and is then transferred to

GLRX5 Glutaredoxin 5, also known as GLRX5, is a protein which in humans is encoded by the ''GLRX5'' gene located on chromosome 14. This gene encodes a mitochondrial protein, which is evolutionarily conserved. It is involved in the biogenesis of iron- ...

in a cysteine desulfurase complex NFS1-LYRM4/ISD11 dependent process. ISCU has two isoforms, isoform 1, which is found in the

and isoform 2, which is found in the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

and

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. T ...

Clinical significance

''ISCU'' mutations have been found in patients with

hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic info ...

mitochondrial myopathy with

and

lactic acidosis Lactic acidosis is a medical condition characterized by a build-up of lactate (especially -lactate) in the body, with formation of an excessively low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive acid accumulates ...

. This disease is a result of a deficiency of ISCU that corresponds to the deficiency of mitochondrial iron-sulfur proteins and impaired

muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of m ...

oxidative metabolism. Characteristics of mitochondrial myopathy with deficiency of ISCU may include lifelong exercise intolerance in which exertion can cause

, dyspnoea, cardiac

palpitations Palpitations are perceived abnormalities of the heartbeat characterized by awareness of cardiac muscle contractions in the chest, which is further characterized by the hard, fast and/or irregular beatings of the heart. Symptoms include a rapi ...

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

, pain of active muscles,

rhabdomyolysis Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of t ...

myoglobinuria Myoglobinuria is the presence of myoglobin in the urine, which usually results from rhabdomyolysis or muscle injury. Myoglobin is present in muscle cells as a reserve of oxygen. Signs and symptoms Signs and symptoms of myoglobinuria are usual ...

, elevated lactate and

pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic ac ...

, decreased

oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...

utilization, large calves, and possibly weakness.

Genetics

This disorder has been associated with several different mutations and is inherited in an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...

manner. It was originally believed to affect only those of northern Swedish ancestry, however the disease has been found in those of Norwegian and Finnish decent as well. The carrier rate in northern Sweden has been estimated at 1:188. ISCU deficiency has been linked to pathogenic variants including

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene ...

ic variants c.418+382G>C, g.7044G>C, and IVS5+382 G>C as well as a c.149G>A

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

3. The intronic mutations have been suggested to activate a cryptic splice site, resulting in the production of a

splice variant Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...

that encodes a putatively non-functional protein.

Interactions

ISCU has been shown to have 235 binary protein-protein interactions including 79 co-complex interactions. ISCU appears to interact with ISCS,

NUP62 Nuclear pore glycoprotein p62 is a protein complex associated with the nuclear envelope. The p62 protein remains associated with the nuclear pore complex-lamina fraction. p62 is synthesized as a soluble cytoplasmic precursor of 61 kDa followed by ...

SDHB Succinate dehydrogenase biquinoneiron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein that in humans is encoded by the ''SDHB'' gene. The succinate dehydrogenase (also called SDH or Comple ...

, HPRT1, CCDC172, GOLGA2, IKZF1, KRT40, AGTRAP, NECAB2, FAM9B, BANP, LNX1, MID2, GOLGA6L9, ccdc136, KRT34, SPERT,

PICK1 Protein Interacting with C Kinase - 1 is a protein that in humans is encoded by the ''PICK1'' gene. Function The protein encoded by this gene contains a PDZ domain, through which it interacts with protein kinase C, alpha (PRKCA). This protein ...

, YWHAB, SFN, mbl, E7, dnaX, hscB, MAPk-Ak2, hale, and cv-c.

References

External links

GeneReviews/NCBI/NIH/UW entry on Myopathy with Deficiency of ISCU

GeneReviews/NIH/NCBI/UW entry on Myopathy with Deficiency of ISCU
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