Trinucleotide and other DNA Repeat Disorders

Diseases and Disorders, Diseases Associated with DNA Abnormalities, Trinucleotide Repeat Disorders

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Last Updated: September 15, 2022

Triplet Expansion Disorders

The trinucleotide repeat disorders (also known as trinucleotide repeat expansion disorders or triplet repeat expansion disorders) represent a family of genetic disorders caused by an increase in the number of trinucleotide repeats in certain genes exceeding the normal, stable threshold. Each gene affected by trinucleotide repeat expansion has a different number of repeats that constitutes the normal threshold and the number that results in manifestation of disease.

The trinucleotide repeat disorders are divided into three categories determined by the type of repeat. The most common repeat is the triplet CAG which when present in the coding region of a gene codes for the amino acid glutamine (Q). Therefore, these disorders are referred to as the polyglutamine (polyQ) disorders.

The second category of repeat expansion disorders either do not involve the CAG triplet in the coding region or the CAG triplet is not in the coding region of the gene or the triplet is not CAG and also is not in the coding region. This second type of trinucleotide repeat disorder is referred to as the non-polyglutamine disorder class. The non-polyglutamine disorders result from repeats (primarily trinucleotide repeats) that reside in the promoter region of the affected gene, within the 5′-untranslated region (5′-UTR), within introns, or within the 3′-UTR.

The third category of trinucleotide repeat expansion disorder consists of the diseases associated with expansion of a polyalanine tract (PA) or alterations in genes harboring a polyalanine tract. There are currently 9 well characterized PA disorders in humans although there are close to 500 genes encoding proteins that harbor stretches of consecutive alanine residues ranging from 4 to 20 amino acids in length. One unique feature of the polyalanine repeat is that it is an imperfect repeat consisting of the nucleotides GCN, where N designates any nucleotide.

Non-Triplet Expansion Disorders

Although trinucleotide repeat expansion encompasses the vast majority of repeat expansion diseases, there are other diseases caused by repeat expansion where the repeat size is four (tetranucleotide), five (pentanucleotide), or 12 (dodecanucleotide) nucleotides in length.

A second genetic cause of myotonic dystrophy, identified as myotonic dystrophy 2 (also identified as dystrophia myotonica 2, Ricker syndrome, or proximal myotonic myopathy) results from the expansion of the tetranucleotide CCTG. The CCTG repeat resides in the first intron of the zinc finger protein 9 (ZNF9) gene. The number of repeats found in the ZNF9 gene in affected individuals has been shown to range from a low of 75 to as many as 11,000.

The particular form of spinocerebellar ataxia identified as type 10 (SCA10) results for the expansion of a pentanucleotide repeat (AATCT) that resides in intron 9 of the ataxin 10 (ATXN10) gene. The number of repeats found in the ATXN10 gene in affected individuals has been shown to range from 280 to well over 4,100.

One form (EPM1A) of the family of at least 22 disorders identified as epilepsy, progressive myoclonic (EPM) results from the expansion of a dodecanucleotide repeat (C4GC4GCG) that resides in the promoter region of the cystatin B (CSTB) gene. In this latter disorder the size of the expansion in affected individuals ranges from 3–17 repeats.

Triplet Expansion Disorders

Polyglutamine Disorders

Non-polyglutamine Disorders

Polyalanine Tract Gene Diseases

  • Blepharophimosis, ptosis and epicanthus inversus (BPES): transcription factor FOXL2 gene
  • Cleidocranial dysplasia (CCD): transcription factor RUNX2 gene
  • Congenital central hypoventilation syndrome (CCHS): homeodomain transcription factor PHOX2B gene
  • Hand–foot–genital syndrome (HFG): homeodomain transcription factor HOXA13 gene
  • Holoprosencephaly type 5 (HPE5): zinc-finger transcription factor ZIC2 gene
  • Oculopharyngeal muscular dystrophy (OPMD): nuclear poly(A)-binding protein (PABPN1) gene
  • Synpolydactyly 1 (SPD): homeodomain transcription factor HOXD13 gene
  • Mental retardation, growth hormone deficiency (MRGH): SRY-related HMG-box transcription factor SOX3 gene
  • Infantile spasm syndrome, X-linked (ISSX: one of 40 early infantile epileptic encephalopathies: EIEE): aristaless related homeobox transcription factor ARX gene

Diseases & Disorders