trinucleotide repeat diseases

The pathological expansion of unstable trinucleotide repeats currently is known to cause about 30 diseases (2003). Trinucleotide repeat expansions may prove to cause pathology through a variety of mechanisms including interference with DNA structure, transcription, RNA-protein interaction and altered protein conformations/interactions.

Trinucleotide expansions cause at least 30 diseases. Many are inherited predominantly through paternal transmissions, which are probably the result of germ-cell-specific mutations. A recent study of testicular germ cells in HD patients revealed that expansions occur in diploid cells before the completion of meiosis. Therefore, expansions are not limited to the late-haploid spermatids, in which the genome is ’sleeping’.

Classification

 (CGG repeats)

• X fragile (FRAXA)
• X fragile (FRAXF)
• FRA11B (Jacobsen syndrome)

 (GCC repeats)

• X fragile (FRAXB)

 (CCG repeats)

• FRA16A

 (GAA repeats)

• Friedreich ataxia (FRDA) (Frataxine)

 (CTG repeats)

• myotonic dystrophy (DM) (DMPK)
• spinocerebellar ataxia 8 (SCA8)

 polyglutamine repeat diseases (CAG repeats)

• Huntington disease
• Kennedy disease (SBMA)
• spinocerebellar ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, SCA17)
• dentatorubral pallidoluysia atrophy (DRPLA)

 polyalanine repeat diseases (GCN repeats)

FOXL2	blepharophimosis-ptosis-epicanthus inversus syndactyly	BPES	MIM.110100
ZIC2	holoprosencephaly 5	HPE5	MIM.609637
PHOX2B	congenital failure of autonomic control	-	MIM.209880
ARX	X-linked infantile spasm syndrome	-	MIM.308350
SOX3	X-linked mental retardation with isolated growth hormone deficiency	MRGH	MIM.300123
RUNX2	cleidocranial dysplasia	CCD	MIM.119600
HOXA13	hand-foot-genital syndrome	HFGS	MIM.140000
HOXD13	synpolydactyly 1	SPD1	MIM.186000
PABPN1	oculopharyngeal muscular dystrophy	OPMD	MIM.164300

References

 Repeat expansion disease: progress and puzzles in disease pathogenesis. La Spada AR, Taylor JP. Nat Rev Genet. 2010 Feb 23. PMID: 20177426

 Orr HT, Zoghbi HY. Trinucleotide repeat disorders. Annu Rev Neurosci. 2007;30:575-621. Review. PMID: 17417937

 Gatchel JR, Zoghbi HY. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet. 2005 Oct;6(10):743-55. PMID: 16205714

 Pearson CE, Edamura KN, Cleary JD. Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet. 2005 Oct;6(10):729-42. PMID: 16205713

 Di Prospero NA, Fischbeck KH. Therapeutics development for triplet repeat expansion diseases. Nat Rev Genet. 2005 Oct;6(10):756-65. PMID: 16205715

 Albrecht A, Mundlos S. The other trinucleotide repeat: polyalanine expansion disorders. Curr Opin Genet Dev. 2005 Jun;15(3):285-93. PMID: 15917204

 Cleary JD, Pearson CE. Replication fork dynamics and dynamic mutations: the fork-shift model of repeat instability. Trends Genet. 2005 May;21(5):272-80. PMID: 15851063

 Amiel J, Trochet D, Clement-Ziza M, Munnich A, Lyonnet S. Polyalanine expansions in human. Hum Mol Genet. 2004 Oct 1;13 Suppl 2:R235-43. PMID: 15358730

 Brown LY, Brown SA. Alanine tracts: the expanding story of human illness and trinucleotide repeats. Trends Genet. 2004 Jan;20(1):51-8. PMID: 14698619

 Pearson CE. Slipping while sleeping? Trinucleotide repeat expansions in germ cells. Trends Mol Med. 2003 Nov;9(11):490-5. PMID: 14604827

 Nag DK. Trinucleotide repeat expansions: timing is everything.
Trends Mol Med. 2003 Nov;9(11):455-7. PMID: 14604819

 Cummings CJ, Zoghbi HY. Fourteen and counting: unraveling trinucleotide repeat diseases. Hum Mol Genet. 2000 Apr 12;9(6):909-16. PMID: 10767314

 Paulson HL, Fischbeck KH. Trinucleotide repeats in neurogenetic disorders. Annu Rev Neurosci. 1996;19:79-107. PMID: 8833437