Huntingtin

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Huntingtin (Huntington disease)
Identifiers
Symbol(s) HTT; IT15; HD
External IDs OMIM: 143100 MGI: 96067 HomoloGene: 1593
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 3064 15194
Ensembl ENSG00000197386 ENSMUSG00000029104
Uniprot P42858 P42859
Refseq NM_002111 (mRNA)
NP_002102 (protein)		 NM_010414 (mRNA)
NP_034544 (protein)
Location Chr 4: 3.05 - 3.22 Mb Chr 5: 35.08 - 35.23 Mb
Pubmed search [1] [2]

The Huntingtin gene, also called HD (Huntington disease) gene, or the IT15 ("interesting transcript 15") gene codes for a 348 kDa protein called huntingtin protein. The exact function of this protein is not known, but it plays an important role in nerve cells. Within cells, huntingtin may be involved in signaling, transporting materials, binding proteins and other structures, and protecting against programmed cell death (apoptosis). The huntingtin protein is required for normal development before birth.[citation needed] It is expressed in many tissues in the body, with the highest levels of expression seen in the brain.

The 5' end of the HD gene has a sequence of 3 DNA bases, cytosine-adenine-guanosine (CAG), coding for the amino acid glutamine, that is repeated multiple times. This region is called a trinucleotide repeat. Normal persons have a CAG repeat count of between 7 and 35 repeats.

The HD gene is located on the short (p) arm of chromosome 4 at position 16.3, from base pair 3,113,411 to base pair 3,282,655.

[edit] Associated Disorders

Main article: Huntington's Disease

Huntington's disease is caused by a mutation in the Huntingtin gene, where the CAG repeats more than 35 times and is unstable. These expanded repeats lead to production of a huntingtin protein that contains an abnormal number of glutamines at the N-terminal. This makes it part of a class of neurodegenerative disorders known as trinucleotide repeat disorders or polyglutamine disorders.

Enzymes in the cell often cut this elongated protein into fragments. The protein fragments form abnormal clumps inside nerve cells and may attract other, normal proteins into the clumps. These nerve cells do not function properly and ultimately die. This process is particularly likely to occur in the striatum (a part of the brain that coordinates movement) primarily, and the frontal cortex (a part of the brain that controls thinking and emotions).

People with 36 to 40 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with more than 40 repeats will develop the disorder during a normal lifetime. When there are more than 100 CAG repeats, the person develops a severe form of HD known as Juvenile HD. Therefore, the number of CAG (the sequence coding for the amino acid glutamine) repeats influences the age of onset of the disease. No case of HD has been diagnosed with a count less than 36.[1]

Effect classification repeat count
unnaffected normal < 27
intermediate 27 - 35
affected Reduced Penetrance 36 - 39
Full Penetrance > 39

As the altered gene is passed from one generation to the next, the size of the CAG repeat expansion can change; it often increases in size, especially when it is inherited from the father. People with 27 to 35 CAG repeats have not been reported to develop the disorder, but their children are at risk of having the disease if the repeat expansion increases.

[edit] References

  • Bates G (2003). "Huntingtin aggregation and toxicity in Huntington's disease". Lancet 361 (9369): 1642–4. doi:10.1016/S0140-6736(03)13304-1. PMID 12747895. 
  • Cattaneo E (2003). "Dysfunction of wild-type huntingtin in Huntington disease". News Physiol Sci 18: 34–7. PMID 12531930. 
  • Gardian G, Vecsei L (2004). "Huntington's disease: pathomechanism and therapeutic perspectives". J Neural Transm 111 (10-11): 1485–94. doi:10.1007/s00702-004-0201-4. PMID 15480847. 
  • Landles C, Bates GP (2004). "Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series". EMBO Rep 5 (10): 958–63. doi:10.1038/sj.embor.7400250. PMID 15459747. 
  • Li SH, Li XJ (2004). "Huntingtin and its role in neuronal degeneration". Neuroscientist 10 (5): 467–75. doi:10.1177/1073858404266777. PMID 15359012. 
  • MacDonald ME (2003). "Huntingtin: alive and well and working in middle management". Sci STKE 2003 (207): pe48. PMID 14600292. 
  • Rangone H, Humbert S, Saudou F (2004). "Huntington's disease: how does huntingtin, an anti-apoptotic protein, become toxic?". Pathol Biol (Paris) 52 (6): 338–42. PMID 15261377. 
  • Young AB (2003). "Huntingtin in health and disease". J Clin Invest 111 (3): 299–302. doi:10.1172/JCI17742. PMID 12569151. 

[edit] External links