X-linked intellectual disability refers to medical disorders associated with

X-linked recessive inheritance ''Main Article'': Sex linkage 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 hemizygous for the gene mutation bec ...

that result in

intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

. 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 chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...

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, and auditory and visual abnormalities. Pres ...

DDX3X syndrome DDX3X syndrome is a genetic disorder that affects predominantly females. Patients with DDX3X syndrome may develop developmental delay or intellectual disability, autism, ADHD, and low muscle tone. The syndrome develops due to mutations of the DDX ...

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 MECP2 duplication syndrome (M2DS) is a rare disease that is characterized by severe intellectual disability and impaired motor function. It is an X-linked recessive inheritance, X-linked genetic disorder caused by the overexpression of MeCP2 prote ...

* 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 (

tetraspanin Tetraspanins are a family of membrane proteins found in all multicellular eukaryotes also referred to as the transmembrane 4 superfamily (TM4SF) proteins. These proteins have four transmembrane alpha-helices and two extracellular domains, one sh ...

s, see TSPAN7). This gene is also associated with neuropsychiatric diseases such as

Huntington's chorea Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly inherited. It typically presents as a triad of progressive psychiatric, cognitive, and motor symptoms. The earliest sympt ...

. * AP1S2: AP-1 complex subunit sigma-2. Adaptor protein complex 1 is found on the cytoplasmic face of vesicles located at the

Golgi complex The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...

, where it mediates both the recruitment of

clathrin Clathrin is a protein that plays a role in the formation of coated vesicles. Clathrin was first isolated by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskel ...

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 An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

of the long-chain fatty-acid-coenzyme A ligase family. It converts free

long-chain fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...

s into

fatty acyl-CoA esters Fatty acyl-CoA esters are fatty acid derivatives formed of one fatty acid, a 3'-phospho-Adenosine monophosphate, AMP linked to phosphorylated pantothenic acid (vitamin B5) and cysteamine. Long-chain acyl-CoA esters are substrates for a number o ...

, and thereby play a key role in

lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

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 a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids and o ...

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

. * ZNF41: 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) superfami ...

: 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 family 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 GUK d ...

(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 pr ...

: 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 F. Lyon, 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 ...

. 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 girls. 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: Aristaless related homeobox, is a protein associated with

and

lissencephaly Lissencephaly (, meaning 'smooth brain') is a set of rare brain disorders whereby the whole or parts of the surface of the brain are smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a ...

. 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 p ...

: Lysine-specific demethylase 5C is an

that in humans is encoded by the ''KDM5C''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

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 Z ...

, 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 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. Structure Most oxygenases contain ...

, and is a

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...

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 activator A transcriptional activator is a protein (transcription factor) that increases transcription of a gene or set of genes. Activators are considered to have ''positive'' control over gene expression, as they function to promote gene transcription and ...

s with a positive action on RNA elongation. AFF2/FMR2, AFF3/LAF4 and AFF4/AF5q31 localize in

nuclear speckle The cell nucleus (; : nuclei) is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, and a few others including osteoc ...

s (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. Clinical significance Mutations of the SLC6A8 gene can cause cerebral creatine deficiency syndrome 1. See also * Sodium:neur ...

: 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 In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene i ...

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 ...

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. Ubiqui ...

* OGT

References

External links

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