X-linked Intellectual Disability
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X-linked intellectual disability refers to medical disorders associated with
X-linked recessive inheritance X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...
that result in
intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...
. As with most X-linked disorders, males are more heavily affected than females. Females with one affected
X chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
and one normal X chromosome tend to have milder symptoms. Unlike many other types of intellectual disability, the genetics of these conditions are relatively well understood. It has been estimated there are ~200 genes involved in this syndrome; of these ~100 have been identified. Many of these genes are found on the short 'p' arm of the chromosome, and duplications at Xp11.2 are associated with the syndromic form of the condition. X-linked intellectual disability accounts for ~16% of all cases of intellectual disability in males.


Syndromes

Several X-linked syndromes include intellectual disability as part of the presentation. These include: *
Coffin–Lowry syndrome Coffin–Lowry syndrome is a genetic disorder that is X-linked dominant and which causes severe mental problems sometimes associated with abnormalities of growth, cardiac abnormalities, kyphoscoliosis, as well as auditory and visual abnormalities. ...
* DDX3X syndrome *
MASA syndrome MASA syndrome is a rare X-linked recessive neurological disorder on the L1 disorder spectrum belonging in the group of hereditary spastic paraplegias a paraplegia known to increase stiffness spasticity in the lower limbs. This syndrome also has t ...
* MECP2 duplication syndrome * Mental retardation and microcephaly with pontine and cerebellar hypoplasia *
X-linked alpha thalassemia mental retardation syndrome Alpha-thalassemia mental retardation syndrome (ATRX), also called alpha-thalassemia X-linked intellectual disability syndrome, nondeletion type or ATR-X syndrome, is an X-linked recessive condition associated with a mutation in the ''ATRX'' gene. ...


List of genes

Following is a list of genes located on the X chromosome and linked to intellectual disability. There are also several loci that have not been associated with a specific gene. * IQSEC2: encodes an exchange factor for the Arf family of small GTP binding proteins, involved in the formation of secretory vesicles. * TM4SF2: is a member of the 4 transmembrane domains family of proteins (tetraspanins, see
TSPAN7 Tetraspanin-7 is a protein that in humans is encoded by the ''TSPAN7'' gene. The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins t ...
). This gene is also associated with neuropsychiatric diseases such as Huntington's chorea. * AP1S2: AP-1 complex subunit sigma-2. Adaptor protein complex 1 is found on the cytoplasmic face of vesicles located at the Golgi complex, where it mediates both the recruitment of clathrin to the membrane and the recognition of sorting signals within the cytosolic tails of transmembrane receptors. *
ACSL4 Long-chain-fatty-acid—CoA ligase 4 is an enzyme that in humans is encoded by the ''ACSL4'' gene. The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, ...
: Long-chain-fatty-acid—CoA ligase 4 is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
of the long-chain
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, fr ...
-
coenzyme A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that ass ...
A
ligase In biochemistry, a ligase is an enzyme that can catalyze the joining (ligation) of two large molecules by forming a new chemical bond. This is typically via hydrolysis of a small pendant chemical group on one of the larger molecules or the enzym ...
family. It converts free long-chain fatty acids into fatty
acyl In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an alkyl group (). In organic chemistry, the acyl group (IUPAC n ...
- CoA
ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
s, and thereby play a key role in
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...
and fatty acid degradation. This isozyme preferentially utilizes
arachidonate Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
as substrate. *
ZNF41 Zinc finger protein 41 is a protein that in humans is encoded by the ''ZNF41'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ' ...
: Zinc finger protein 41 is a likely zinc finger family transcription factor. *
DLG3 Disks large homolog 3 (DLG3) also known as neuroendocrine-DLG or synapse-associated protein 102 (SAP-102) is a protein that in humans is encoded by the ''DLG3'' gene. DLG3 is a member of the membrane-associated guanylate kinase (MAGUK) superfamily ...
: Disks large homolog 3, also named neuroendocrine-DLG or synapse-associated protein 102 (SAP-102). DLG3 is a member of the
membrane-associated guanylate kinase The membrane-associated guanylate kinases (MAGUK) are a superfamily of proteins. The MAGUKs are defined by their inclusion of PDZ, SH3 and GUK domains, although many of them also contain regions homologous of CaMKII, WW and L27 domains. The G ...
(MAGUK) superfamily. * FTSJ1: Transfert RNA methyltransferase 1 is a member of the S-adenosylmethionine-binding protein family. This nucleolar protein is involved in the processing and modification of tRNA. *
GDI1 Rab GDP dissociation inhibitor alpha is a protein that in humans is encoded by the ''GDI1'' gene. Function GDP dissociation inhibitors are proteins that regulate the GDP-GTP exchange reaction of members of the rab family, small GTP-binding pro ...
: RabGDI alpha makes a complex with geranylgeranylated small GTP-binding proteins of the Rab family and keeps them in the cytosol. *
MECP2 ''MECP2'' (methyl CpG binding protein 2) is a gene that encodes the protein MECP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in ...
: methyl CpG binding protein 2 is a transcription regulator, which represses transcription from methylated gene promoters. It appears to be essential for the normal function of nerve cells. In contrast to other MBD family members, MECP2 is X-linked and subject to
X inactivation X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a ...
. MECP2 gene mutations are the cause of most cases of
Rett syndrome Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in females. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often h ...
, a progressive neurologic developmental disorder and one of the most common causes of intellectual disability in women. *
ARX Arx, ARX, or ArX may refer to: *ARX (Algorithmic Research Ltd.), a digital security company *ARX (gene), Aristaless related homeobox *ARX (operating system), an operating system *ArX (revision control), revision control software *Arx (Roman), a Ro ...
: Aristaless related homeobox, is a protein associated with
intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...
and
lissencephaly Lissencephaly (, meaning "smooth brain") is a set of rare brain disorders whereby the whole or parts of the surface of the brain appear smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation resulting in ...
. This gene is a homeobox-containing gene expressed during development. The expressed protein contains two conserved domains, a C-peptide (or aristaless domain) and the prd-like class homeobox domain. It is a member of the group-II aristaless-related protein family whose members are expressed primarily in the central and/or peripheral nervous system. This gene is involved in CNS and pancreas development. Mutations in this gene cause X-linked intellectual disability and epilepsy. *
KDM5C Lysine-specific demethylase 5C is an enzyme that in humans is encoded by the ''KDM5C'' gene. KDM5C belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily. Function This gene is a member of the SMCY homolog family and encodes a pr ...
: Lysine-specific demethylase 5C is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the ''KDM5C''
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 ba ...
a member of the SMCY homolog family and encodes a protein with one
ARID domain In molecular biology, the ARID domain (AT-rich interaction domain; also known as BRIGHT (B-cell Regulator of Ig Heavy chain Transcription) domain)) is a protein domain that binds to DNA. ARID domain-containing proteins are found in fungi, plants ...
, one JmjC domain, one JmjN domain and two PHD-type zinc fingers. The DNA-binding motifs suggest this protein is involved in the regulation of transcription and chromatin remodeling. *
PHF8 PHD finger protein 8 is a protein that in humans is encoded by the ''PHF8'' gene. Function PHF8 belongs to the family of ferrous iron and alpha-ketoglutarate-dependent hydroxylases superfamily., and is active as a histone lysine demethylase wi ...
: PHD finger protein 8 belongs to the family of ferrous iron and 2-oxoglutarate dependent
oxygenases An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 (as in air) to it. The oxygenases form a class of oxidoreductases; their EC number is EC 1.13 or EC 1.14. Discoverers Oxygenases were disco ...
, and is a
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
lysine demethylase with selectivity for the di-and monomethyl states. * FMR2: Fragile mental retardation 2 (FMR2: synonym AFF2), the protein belongs to the AFF family which currently has four members: AFF1/ AF4, AFF2/FMR2, AFF3/ LAF4 and AFF4/ AF5q31. All AFF proteins are localized in the nucleus and have a role as transcriptional activators with a positive action on RNA elongation. AFF2/FMR2, AFF3/LAF4 and AFF4/AF5q31 localize in nuclear speckles (subnuclear structures considered to be storage/modification sites of pre-mRNA splicing factors) and are able to bind RNA with a high apparent affinity for the G-quadruplex structure. They appear to modulate alternative splicing via the interaction with the G-quadruplex RNA-forming structure. *
Slc6a8 Sodium- and chloride-dependent creatine transporter 1 is a protein that in humans is encoded by the ''SLC6A8'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity ...
: Creatine transporter is a protein that is required for creatine to enter the cell. Creatine is essential for maintaining ATP levels in cells with a high energy demand. *
GSPT2 Eukaryotic peptide chain release factor GTP-binding subunit ERF3B is an enzyme that in humans is encoded by the ''GSPT2'' gene. GSPT2 is closely related to GSPT1 (MIM 139259), a GTP-binding protein that plays an essential role at the G1- to S-pha ...
*
MAGED1 Melanoma-associated antigen D1 is a protein that in humans is encoded by the ''MAGED1'' gene. Function This gene is a member of the melanoma antigen gene (MAGE) family. Most of the genes of this family encode tumor specific antigens that are n ...
*
UBE2A Ubiquitin-conjugating enzyme E2 A is a protein that in humans is encoded by the ''UBE2A'' gene. The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquit ...


See also

* Xp11.2 Duplication


References


External links

{{Vesicular transport protein disorders Intellectual disability X-linked recessive disorders