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X-linked intellectual disability

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Title: X-linked intellectual disability  
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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.


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: Putative ribosomal RNA methyltransferase 1 is a member of the S-adenosylmethionine-binding protein family. This nucleolar protein may be involved in the processing and modification of rRNA.[12]
  • 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.[13] 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.[14]
  • 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.[15]
  • PHF8: PHD finger protein 8 belongs to the family of ferrous iron and 2-oxoglutarate dependent oxygenases,[16] and is an histone lysine demethylase with selectivity for the di-and monomethyl states.[17]
  • FMR2: Fragile Mental Retardation 2 (FMR2: synonym AFF2),[18] the protein belongs to the AFF family which currently has four members: AFF1/AF4, AFF2/FMR2, AFF3/LAF4 and AFF4/AF5q31.[19] 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.[20]


  1. ^ "Fragile X Syndrome - X-linked Mental Retardation and Macroorchidism". International Birth Defect Information Systems. Retrieved 2010-12-10. 
  2. ^ Ropers, H. -H.; Hamel, B. C. J. (2005). "X-linked mental retardation". Nature Reviews Genetics 6 (1): 46–57.  
  3. ^ 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.  
  4. ^ 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.  
  5. ^ 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.  
  6. ^ 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.  
  7. ^ 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.  
  8. ^ "Entrez Gene: AP1S2 adaptor-related protein complex 1, sigma 2 subunit". 
  9. ^ 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.  
  10. ^ 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.  
  11. ^ 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.  
  12. ^ 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.  
  13. ^ Chahrour M, et al. (2008). "MeCP2, a key contributor to neurological disease, activates and represses transcription". Science 320 (5880): 1224–9.  
  14. ^ 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.  
  15. ^ 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.  
  16. ^ Loenarz, C.; Schofield, C. J. (2008). "Expanding chemical biology of 2-oxoglutarate oxygenases". Nat. Chem. Biol. 4 (3): 152–156.  
  17. ^ 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.  
  18. ^ 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.  
  19. ^ 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.  
  20. ^ 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.  
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