SLC22A5 is a
membrane transport protein
A membrane transport protein (or simply transporter) is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembra ...
associated with
primary carnitine deficiency. This protein is involved in the active cellular uptake of
carnitine. It acts a
symporter, moving sodium
ions
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...
and other organic
cations
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by con ...
across the membrane along with carnitine. Such polyspecific
organic cation transporters in the liver, kidney, intestine, and other organs are critical for the elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins.
Mutations in the ''SLC22A5'' gene cause
systemic primary carnitine deficiency, which can lead to
heart failure.
Structure
The ''SLC22A5'' gene, containing 10 exons,
[Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: : : . World Wide Web URL: https://omim.org/] is located on the q arm of
chromosome 5
Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs (the building blocks of DNA) and represents almost 6% of the total DNA in cells. C ...
in position 31.1 and spans 25,910 base pair.
The gene produces a 63 kDa protein composed of 557
amino acids.
The protein has 12 putative
transmembrane domains
A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid b ...
, with a long extracellular loop of 107 amino acids between the first two transmembrane domains and an intracellular loop between the fourth and fifth transmembrane domains. This long extracellular loop has three potential sites for
N-glycosylation
''N''-linked glycosylation, is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom (the amide nitrogen of an asparagine (Asn) residue of a protein), ...
, and the intracellular loop has an
ATP/GTP binding motif. In putative intracellular domains, there are five potential sites for
protein-kinase C-dependent phosphorylation and one for
protein-kinase A-dependent phosphorylation.
Function
The ''SLC22A5'' gene codes for a plasma
integral membrane protein
An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a sign ...
which functions as both an
organic cation transporter and a sodium-dependent high affinity
carnitine transporter.
The encoded protein is involved in the active cellular uptake of carnitine, transporting one
sodium ion with one molecule of carnitine. Organic cations transported by this protein include
tetraethylammonium
Tetraethylammonium (TEA), () or (Et4N+) is a quaternary ammonium cation consisting of four ethyl groups attached to a central nitrogen atom, and is positively charged. It is a counterion used in the research laboratory to prepare lipophilic salts ...
(TEA) without involvement of sodium. The relative uptake activity ratio of carnitine to TEA is 11.3.
Clinical Significance
The main
phenotypical
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological prop ...
effect of autosomal recessive mutations, either
compound heterozygous In medical genetics, compound heterozygosity is the condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disorders, genetic disease in a heterozygous state; that is, an organism is a compound h ...
or
homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
,
in the ''SLC22A5'' gene is
systemic primary carnitine deficiency,
characterized by impaired carnitine transport, urinary carnitine wasting, low serum carnitine levels, reduced intracellular carnitine accumulation, impaired
beta oxidation
In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cyc ...
, and
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 mitochondri ...
ic
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
accumulation.
Patients often display metabolic decompensation,
hypoketotic hypoglycemia,
hepatic encephalopathy
Hepatic encephalopathy (HE) is an altered level of consciousness as a result of liver failure. Its onset may be gradual or sudden. Other symptoms may include movement problems, changes in mood, or changes in personality. In the advanced stage ...
,
Reye syndrome
Reye syndrome is a rapidly worsening brain disease. Symptoms of Reye syndrome may include vomiting, personality changes, confusion, seizures, and loss of consciousness. While liver toxicity typically occurs in the syndrome, jaundice usuall ...
, and
sudden infant death in their first year, followed by the later onset of
cardiomyopathy or
skeletal myopathy,
arrhythmias
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
, muscle weakness, and heart failure in early childhood.
Patients may be
asymptomatic, with about 70% of asymptomatic patients having 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 ...
or
in-frame deletion;
nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...
frequency is increased in symptomatic patients. The symptoms and outcome of the disease can be drastically improved by replacement therapy with L-carnitine. The estimated incidence of primary carnitine deficiency in newborns is about 1 in 40,000.
Interactions
SLC22A5
interacts with
PDZK1
Na(+)/H(+) exchange regulatory cofactor NHE-RF3 is a protein that in humans is encoded by the ''PDZK1'' gene.
Interactions
PDZK1 has been shown to interact with:
* AKAP10,
* CLCN3,
* Cystic fibrosis transmembrane conductance regulator
* FARP ...
.
See also
*
Solute carrier family
References
Further reading
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External links
*
Primary Carnitine Deficiency (OCTN2 database)
{{Membrane transport proteins
Solute carrier family
Amphetamine