X-linked intellectual disability

X-linked intellectual disability
Classification and external resources
MeSH	D038901

X-linked intellectual disability (previously known as X-linked mental retardation) refers to forms of intellectual disability which are specifically associated with X-linked recessive inheritance.

As with most X-linked disorders, males are more heavily affected than females.^[1] Females with one affected X chromosome 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.^[2]^[3] It has been estimated there are ~200 genes involved in this syndrome; of these ~100 have been identified.^[4]

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, MASA syndrome, X-linked alpha thalassemia mental retardation syndrome, and mental retardation and microcephaly with pontine and cerebellar hypoplasia.

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.^[5]
TM4SF2: is a member of the 4 transmembrane domains family of proteins (tetraspanins, see TSPAN7). This gene is also associated with neuropsychiatric diseases such as Huntington's chorea.^[6]
AP1S2: AP-1 complex subunit sigma-2.^[7]^[8] 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 of the long-chain fatty-acid-coenzyme A ligase family. It converts free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation.^[9] This isozyme preferentially utilizes arachidonate as substrate.
ZNF41: Zinc finger protein 41 is a likely zinc finger family transcription factor.^[10]
DLG3: Disks large homolog 3, also named neuroendocrine-DLG or synapse-associated protein 102 (SAP-102).^[11] DLG3 is a member of the membrane-associated guanylate kinase (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.^[12]^[13]
GDI1: RabGDI alpha makes a complex with geranylgeranylated small GTP-binding proteins of the Rab family and keeps them in the cytosol.
MECP2: 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.^[14] In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 gene mutations are the cause of most cases of Rett syndrome, 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 intellectual disability and lissencephaly. 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.^[15]
JARID1C: Lysine-specific demethylase 5C is an enzyme that in humans is encoded by the KDM5C gene a member of the SMCY homolog family and encodes a protein with one ARID domain, 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.^[16]
PHF8: PHD finger protein 8 belongs to the family of ferrous iron and 2-oxoglutarate dependent oxygenases,^[17] and is an histone lysine demethylase with selectivity for the di-and monomethyl states.^[18]
FMR2: Fragile mental retardation 2 (FMR2: synonym AFF2),^[19] the protein belongs to the AFF family which currently has four members: AFF1/AF4, AFF2/FMR2, AFF3/LAF4 and AFF4/AF5q31.^[20] 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: 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.^[21]

References

↑ "Fragile X Syndrome - X-linked Mental Retardation and Macroorchidism". International Birth Defect Information Systems. Retrieved 2010-12-10.
↑ Ropers, H. -H.; Hamel, B. C. J. (2005). "X-linked mental retardation". Nature Reviews Genetics. 6 (1): 46–57. doi:10.1038/nrg1501. PMID 15630421.
↑ Lugtenberg, D.; Veltman, J. A.; Van Bokhoven, H. (2007). "High-resolution genomic microarrays for X-linked mental retardation". Genetics in Medicine. 9 (9): 560–565. doi:10.1097/GIM.0b013e318149e647. PMID 17873643.
↑ Stevenson, R. E.; Schwartz, C. E. (2009). "X-linked intellectual disability: Unique vulnerability of the male genome". Developmental Disabilities Research Reviews. 15 (4): 361–368. doi:10.1002/ddrr.81. PMID 20014364.
↑ Shoubridge C, Tarpey PS, Abidi F, Ramsden SL, Rujirabanjerd S, Murphy JA, Boyle J, Shaw M, Gardner A, Proos A, Puusepp H, Raymond FL, Schwartz CE, Stevenson RE, Turner G, Field M, Walikonis RS, Harvey RJ, Hackett A, Futreal PA, Stratton MR, Gécz J (June 2010). "Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability". Nat. Genet. 42 (6): 486–8. doi:10.1038/ng.588. PMID 20473311.
↑ Abidi FE, Holinski-Feder E, Rittinger O, Kooy F, Lubs HA, Stevenson RE, Schwartz CE (Jun 2002). "A novel 2 bp deletion in the TM4SF2 gene is associated with MRX58". J Med Genet. 39 (6): 430–3. doi:10.1136/jmg.39.6.430. PMC 1735161. PMID 12070254.
↑ Tarpey PS, Stevens C, Teague J, Edkins S, O'Meara S, Avis T, Barthorpe S, Buck G, Butler A, Cole J, Dicks E, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, West S, Widaa S, Yates A, Catford R, Butler J, Mallya U, Moon J, Luo Y, Dorkins H, Thompson D, Easton DF, Wooster R, Bobrow M, Carpenter N, Simensen RJ, Schwartz CE, Stevenson RE, Turner G, Partington M, Gecz J, Stratton MR, Futreal PA, Raymond FL (Dec 2006). "Mutations in the Gene Encoding the Sigma 2 Subunit of the Adaptor Protein 1 Complex, AP1S2, Cause X-Linked Mental Retardation". Am J Hum Genet. 79 (6): 1119–24. doi:10.1086/510137. PMC 1698718. PMID 17186471.
↑ "Entrez Gene: AP1S2 adaptor-related protein complex 1, sigma 2 subunit".
↑ Piccini M, Vitelli F, Bruttini M, Pober BR, Jonsson JJ, Villanova M, Zollo M, Borsani G, Ballabio A, Renieri A (Apr 1998). "FACL4, a new gene encoding long-chain acyl-CoA synthetase 4, is deleted in a family with Alport syndrome, elliptocytosis, and mental retardation". Genomics. 47 (3): 350–8. doi:10.1006/geno.1997.5104. PMID 9480748.
↑ Franze A, Archidiacono N, Rocchi M, Marino M, Grimaldi G (Jul 1991). "Isolation and expression analysis of a human zinc finger gene (ZNF41) located on the short arm of the X chromosome". Genomics. 9 (4): 728–36. doi:10.1016/0888-7543(91)90367-N. PMID 2037297.
↑ Stathakis DG, Lee D, Bryant PJ (Aug 1998). "DLG3, the gene encoding human neuroendocrine Dlg (NE-Dlg), is located within the 1.8-Mb dystonia-parkinsonism region at Xq13.1". Genomics. 49 (2): 310–3. doi:10.1006/geno.1998.5243. PMID 9598320.
↑ Ramser J, Winnepenninckx B, Lenski C, Errijgers V, Platzer M, Schwartz CE, Meindl A, Kooy RF (Sep 2004). "A splice site mutation in the methyltransferase gene FTSJ1 in Xp11.23 is associated with non-syndromic mental retardation in a large Belgian family (MRX9)". J Med Genet. 41 (9): 679–83. doi:10.1136/jmg.2004.019000. PMC 1735884. PMID 15342698.
↑ Guy, MP & Phizicky, EM. (Oct 2014). "Conservation of an intricate circuit for crucial modifications of the tRNAPhe anticodon loop in eukaryotes". rna. 21: 61–74. doi:10.1261/rna.047639.114. PMID 25404562.
↑ Chahrour M, et al. (2008). "MeCP2, a key contributor to neurological disease, activates and represses transcription". Science. 320 (5880): 1224–9. doi:10.1126/science.1153252. PMC 2443785. PMID 18511691.
↑ Bienvenu T, Poirier K, Friocourt G, et al. (2003). "ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation". Hum. Mol. Genet. 11 (8): 981–91. doi:10.1093/hmg/11.8.981. PMID 11971879.
↑ Jensen LR (2005). "Mutations in the JARID1C Gene, Which Is Involved in Transcriptional Regulation and Chromatin Remodeling, Cause X-Linked Mental Retardation". Am. J. Hum. Genet. 76 (2): 227–36. doi:10.1086/427563. PMC 1196368. PMID 15586325.
↑ Loenarz, C.; Schofield, C. J. (2008). "Expanding chemical biology of 2-oxoglutarate oxygenases". Nat. Chem. Biol. 4 (3): 152–156. doi:10.1038/nchembio0308-152. PMID 18277970.
↑ Loenarz, C.; Ge, W.; Coleman, M. L.; Rose, N. R.; Cooper, C. D. O.; Klose, R. J.; Ratcliffe, P. J.; Schofield, C. J. (2009). "PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an N{varepsilon}-dimethyl lysine demethylase". Hum. Mol. Genet. 19 (2): 217–22. doi:10.1093/hmg/ddp480. PMID 19843542.
↑ Stettner GM, Shoukier M, Höger C, Brockmann K, Auber B (August 2011). "Familial intellectual disability and autistic behavior caused by a small FMR2 gene deletion". Am. J. Med. Genet. A. 155A (8): 2003–7. doi:10.1002/ajmg.a.34122. PMID 21739600.
↑ Melko M, Douguet D, Bensaid M, et al. (May 2011). "Functional characterization of the AFF (AF4/FMR2) family of RNA-binding proteins: insights into the molecular pathology of FRAXE intellectual disability". Hum. Mol. Genet. 20 (10): 1873–85. doi:10.1093/hmg/ddr069. PMID 21330300.
↑ Cecil, KM; Salomons, GS; Ball, WS, Jr; Wong, B; Chuck, G; Verhoeven, NM; Jakobs, C; DeGrauw, TJ (Mar 2001). "Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect?". Annals of Neurology. 49 (3): 401–4. doi:10.1002/ana.79. PMID 11261517.

Sex linkage: X-linked disorders

X-linked recessive

Immune	Chronic granulomatous disease (CYBB) Wiskott–Aldrich syndrome X-linked severe combined immunodeficiency X-linked agammaglobulinemia Hyper-IgM syndrome type 1 IPEX X-linked lymphoproliferative disease Properdin deficiency

Hematologic	Haemophilia A Haemophilia B X-linked sideroblastic anemia

Endocrine	Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy KAL1 Kallmann syndrome X-linked adrenal hypoplasia congenita

Metabolic	Amino acid: Ornithine transcarbamylase deficiency Oculocerebrorenal syndrome Dyslipidemia: Adrenoleukodystrophy Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency Pyruvate dehydrogenase deficiency Danon disease/glycogen storage disease Type IIb Lipid storage disorder: Fabry's disease Mucopolysaccharidosis: Hunter syndrome Purine-pyrimidine metabolism: Lesch–Nyhan syndrome Mineral: Menkes disease/Occipital horn syndrome

Nervous system	X-linked mental retardation: Coffin–Lowry syndrome MASA syndrome Alpha-thalassemia mental retardation syndrome Siderius X-linked mental retardation syndrome Eye disorders: Color blindness (red and green, but not blue) Ocular albinism (1) Norrie disease Choroideremia Other: Charcot–Marie–Tooth disease (CMTX2-3) Pelizaeus–Merzbacher disease SMAX2

Skin and related tissue	Dyskeratosis congenita Hypohidrotic ectodermal dysplasia (EDA) X-linked ichthyosis X-linked endothelial corneal dystrophy

Neuromuscular	Becker's muscular dystrophy/Duchenne Centronuclear myopathy (MTM1) Conradi–Hünermann syndrome Emery–Dreifuss muscular dystrophy 1

Urologic	Alport syndrome Dent's disease X-linked nephrogenic diabetes insipidus

Bone/tooth	AMELX Amelogenesis imperfecta

No primary system	Barth syndrome McLeod syndrome Smith–Fineman–Myers syndrome Simpson–Golabi–Behmel syndrome Mohr–Tranebjærg syndrome Nasodigitoacoustic syndrome

X-linked dominant

X-linked hypophosphatemia Focal dermal hypoplasia Fragile X syndrome Aicardi syndrome Incontinentia pigmenti Rett syndrome CHILD syndrome Lujan–Fryns syndrome Orofaciodigital syndrome 1 Craniofrontonasal dysplasia

Cell membrane protein disorders (other than Cell surface receptor, enzymes, and cytoskeleton)

Arrestin

Oguchi disease 1

Myelin

Pulmonary surfactant

Surfactant metabolism dysfunction 1, 2

Cell adhesion molecule

IgSF CAM:

OFC7

Cadherin:	DSG1 Striate palmoplantar keratoderma 1

DSG2 Arrhythmogenic right ventricular dysplasia 10 DSG4 LAH1 DSC2 Arrhythmogenic right ventricular dysplasia 11

Integrin:

cell surface receptor deficiencies

Tetraspanin

Other

See also other cell membrane proteins

Deficiencies of intracellular signaling peptides and proteins

GTP-binding protein regulators

GTPase-activating protein	Neurofibromatosis type I Watson syndrome Tuberous sclerosis

Guanine nucleotide exchange factor	Marinesco–Sjögren syndrome Aarskog–Scott syndrome Juvenile primary lateral sclerosis X-Linked mental retardation 1

G protein

Heterotrimeic	cAMP/GNAS1: Pseudopseudohypoparathyroidism Progressive osseous heteroplasia Pseudohypoparathyroidism Albright's hereditary osteodystrophy McCune–Albright syndrome CGL 2

Monomeric	RAS: HRAS Costello syndrome KRAS Noonan syndrome 3 KRAS Cardiofaciocutaneous syndrome RAB: RAB7 Charcot–Marie–Tooth disease RAB23 Carpenter syndrome RAB27 Griscelli syndrome type 2 RHO: RAC2 Neutrophil immunodeficiency syndrome ARF: SAR1B Chylomicron retention disease ARL13B Joubert syndrome 8 ARL6 Bardet–Biedl syndrome 3

MAP kinase

Cardiofaciocutaneous syndrome

Other kinase/phosphatase

Tyrosine kinase	BTK X-linked agammaglobulinemia ZAP70 ZAP70 deficiency

Serine/threonine kinase	RPS6KA3 Coffin-Lowry syndrome CHEK2 Li-Fraumeni syndrome 2 IKBKG Incontinentia pigmenti STK11 Peutz–Jeghers syndrome DMPK Myotonic dystrophy 1 ATR Seckel syndrome 1 GRK1 Oguchi disease 2 WNK4/WNK1 Pseudohypoaldosteronism 2

Tyrosine phosphatase	PTEN Bannayan–Riley–Ruvalcaba syndrome Lhermitte–Duclos disease Cowden syndrome Proteus-like syndrome MTM1 X-linked myotubular myopathy PTPN11 Noonan syndrome 1 LEOPARD syndrome Metachondromatosis

Signal transducing adaptor proteins

Other

NF2
- Neurofibromatosis type II
NOTCH3
- CADASIL
PRKAR1A
- Carney complex
PRKAG2
- Wolff–Parkinson–White syndrome
PRKCSH
- PRKCSH Polycystic liver disease
XIAP
- XIAP2

See also intracellular signaling peptides and proteins

Genetic disorder, protein biosynthesis: Transcription factor/coregulator deficiencies

(1) Basic domains

1.2	Feingold syndrome Saethre–Chotzen syndrome

1.3	Tietz syndrome

(2) Zinc finger
DNA-binding domains

2.1	(Intracellular receptor): Thyroid hormone resistance Androgen insensitivity syndrome PAIS MAIS CAIS Kennedy's disease PHA1AD pseudohypoaldosteronism Estrogen insensitivity syndrome X-linked adrenal hypoplasia congenita MODY 1 Familial partial lipodystrophy 3 SF1 XY gonadal dysgenesis

2.2	Barakat syndrome Tricho–rhino–phalangeal syndrome

2.3	Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome Denys–Drash syndrome Duane-radial ray syndrome MODY 7 MRX 89 Townes–Brocks syndrome Acrocallosal syndrome Myotonic dystrophy 2

2.5	Autoimmune polyendocrine syndrome type 1

(3) Helix-turn-helix domains

3.1	ARX Ohtahara syndrome Lissencephaly X2 MNX1 Currarino syndrome HOXD13 SPD1 Synpolydactyly PDX1 MODY 4 LMX1B Nail–patella syndrome MSX1 Tooth and nail syndrome OFC5 PITX2 Axenfeld syndrome 1 POU4F3 DFNA15 POU3F4 DFNX2 ZEB1 Posterior polymorphous corneal dystrophy Fuchs' dystrophy 3 ZEB2 Mowat–Wilson syndrome

3.2	PAX2 Papillorenal syndrome PAX3 Waardenburg syndrome 1&3 PAX4 MODY 9 PAX6 Gillespie syndrome Coloboma of optic nerve PAX8 Congenital hypothyroidism 2 PAX9 STHAG3

3.3	FOXC1 Axenfeld syndrome 3 Iridogoniodysgenesis, dominant type FOXC2 Lymphedema–distichiasis syndrome FOXE1 Bamforth–Lazarus syndrome FOXE3 Anterior segment mesenchymal dysgenesis FOXF1 ACD/MPV FOXI1 Enlarged vestibular aqueduct FOXL2 Premature ovarian failure 3 FOXP3 IPEX

3.5	IRF6 Van der Woude syndrome Popliteal pterygium syndrome

(4) β-Scaffold factors
with minor groove contacts

4.2	Hyperimmunoglobulin E syndrome

4.3	Holt–Oram syndrome Li–Fraumeni syndrome Ulnar–mammary syndrome

4.7	Campomelic dysplasia MODY 3 MODY 5 SF1 SRY XY gonadal dysgenesis Premature ovarian failure 7 SOX10 Waardenburg syndrome 4c Yemenite deaf-blind hypopigmentation syndrome

4.11	Cleidocranial dysostosis

(0) Other transcription factors

0.6	Kabuki syndrome

Ungrouped

Transcription coregulators

Coactivator:	CREBBP Rubinstein–Taybi syndrome

Corepressor:	HR (Atrichia with papular lesions)

Inherited disorders of trafficking / vesicular transport proteins

Vesicle formation

Lysosome/Melanosome:	HPS1-HPS7 Hermansky–Pudlak syndrome LYST Chédiak–Higashi syndrome

COPII:	SEC23A Cranio–lenticulo–sutural dysplasia

COG7 CDOG IIE

APC:	AP1S2 X-linked intellectual disability AP3B1 Hermansky–Pudlak syndrome 2 AP4M1 CPSQ3

Rab

ARL6 BBS3

RAB27A Griscelli syndrome 2

CHM Choroideremia MLPH Griscelli syndrome 3

Cytoskeleton

Myosin:	MYO5A Griscelli syndrome 1

Microtubule:	SPG4 Hereditary spastic paraplegia 4

Kinesin:	KIF5A Hereditary spastic paraplegia 10

Spectrin:	SPTBN2 Spinocerebellar ataxia 5

Vesicle fusion

Synaptic vesicle:	SNAP29 CEDNIK syndrome STX11 Hemophagocytic lymphohistiocytosis 4

Caveolae:	CAV1 Congenital generalized lipodystrophy 3 CAV3 Limb-girdle muscular dystrophy 2B, Long QT syndrome 9

Vacuolar protein sorting:	VPS33B ARC syndrome VPS13B Cohen syndrome

DYSF Distal muscular dystrophy

See also vesicular transport proteins

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