Monocarboxylate transporter 8 (MCT8) is an active transporter
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''SLC16A2''
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 b ...
.
Function
MCT8 actively transports a variety of iodo-
thyronines including the thyroid hormones
T3 and
T4.
Clinical significance
A genetic disorder (discovered in 2003
and 2004
) is caused by mutation in the transporter of thyroid hormone, MCT8, also known as SLC16A2, is believed to be account for a significant fraction of the undiagnosed neurological disorders (usually resulting in
hypotonic
In chemical biology, tonicity is a measure of the effective osmotic pressure gradient; the water potential of two solutions separated by a partially-permeable cell membrane. Tonicity depends on the relative concentration of selective membrane-imp ...
/floppy infants with delayed milestones). This genetic defect was known as
Allan–Herndon–Dudley syndrome (since 1944) without knowing its actual cause. It has been shown mutated in cases of X-linked
leukoencephalopathy Leukoencephalopathy (leukodystrophy-like diseases) is a term that describes all of the brain white matter diseases, whether their molecular cause is known or unknown. It can refer specifically to any of these diseases:
*Progressive multifocal leuko ...
.
Some of the symptoms for this disorder as are follows: normal to slightly elevated
TSH, elevated T
3 and reduced T
4 (ratio of T
3/T
4 is about double its normal value). Normal looking at birth and for the first few years, hypotonic (floppy), in particular difficulty to hold the head, possibly difficulty to thrive, possibly with delayed myelination (if so, some cases are reported with an MRI pattern similar to
Pelizaeus–Merzbacher disease, known as PMD
), possibly with decreased mitochondrial enzyme activities, possibly with fluctuating
lactate
Lactate may refer to:
* Lactation, the secretion of milk from the mammary glands
* Lactate, the conjugate base of lactic acid
Lactic acid is an organic acid. It has a molecular formula . It is white in the solid state and it is miscible with w ...
level. Patients have an alert face, a limited IQ, patients may never talk/walk, 50% need feeding tube, patients have a normal life span. This disease can be ruled out with a simple TSH/T
4/T
3 thyroid test.
Model organisms
Mice
A conditional
knockout mouse
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
line, called ''Slc16a2
tm1a(KOMP)Wtsi''
was generated as part of the
International Knockout Mouse Consortium
The International Knockout Mouse Consortium (IKMC) is a scientific endeavour to produce a collection of mouse embryonic stem cell lines that together lack every gene in the genome, and then to distribute the cells to scientific researchers to cr ...
program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized
phenotypic screen
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 ...
to determine the effects of deletion.
Twenty one tests were carried out on
mutant
In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...
mice and three significant abnormalities were observed.
Female
homozygote
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 ...
mutants had decreased circulating glucose levels. Male
hemizygous
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 ...
mutants had an increased susceptibility to
bacterial infection
Pathogenic bacteria are bacteria that can cause disease. This article focuses on the bacteria that are pathogenic to humans. Most species of bacteria are harmless and are often beneficial but others can cause infectious diseases. The number ...
. Both sexes had various abnormal plasma chemistry parameters.
Zebrafish
A knockout
zebrafish
The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ca ...
line was generated in 2014 using the
zinc-finger nuclease (ZFN)-mediated targeted gene editing system. Similar to human patients, ''the'' zebrafish larvae exhibited neurological and behavioral deficiencies. They demonstrated reduced locomotor activity, altered
myelin
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can ...
-related genes and neuron-specific deficiencies in circuit formation.
Xenopus
Expression of ''mct8'' has been characterised in ''
Xenopus laevis
The African clawed frog (''Xenopus laevis'', also known as the xenopus, African clawed toad, African claw-toed frog or the ''platanna'') is a species of African aquatic frog of the family Pipidae. Its name is derived from the three short claws o ...
'' and ''
Xenopus tropicalis''.
See also
*
Solute carrier family
References
Further reading
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{{Membrane transport proteins
Solute carrier family
Genes mutated in mice