Molecular Pathogenesis
As in other polyglutamine disorders, the disease-causing CAG expansion in DRPLA (ATN1) led to the identification of neuronal intranuclear protein aggregates, or intranuclear inclusions (NIIs) in the brains of affected individuals [Hayashi et al 1998, Igarashi et al 1998, Mori et al 2012a, Mori et al 2012b]. Accumulation of abnormal DRPLA protein (atrophin-1) in the neuronal nuclei is the predominant neuropathologic finding. Of note, NIIs are observed in central nervous system regions far beyond the systems previously reported to be affected on conventional neuropathologic findings. It has been suggested that NIIs are responsible for clinical features such as dementia and epilepsy [Yamada et al 2000, Yamada et al 2001, Yamada et al 2002].
Animal models. Studies of mouse models suggest that neuronal dysfunction without neuronal death is the essential pathophysiologic process and that age-dependent neuronal intranuclear accumulation (NIA) underlies the neuronal dysfunction in DRPLA.
Mouse models for DRPLA expressing full-length human ATN1 with CAG expansion have been created [Sato et al 1999b, Sato et al 2009].
Mice expressing 76 CAG repeats exhibited intergenerational instability of CAG repeats (as similarly observed in families with DRPLA), but no obvious neurologic phenotypes. Mice with 129 CAG repeats exhibited devastating progressive neurologic phenotypes similar to individuals with juvenile-onset DRPLA. Neurologic dysfunction of the globus pallidus (GP) and cerebellum was observed, as well as progressive shrinkage of distal dendrites of Purkinje cells (PCs) and progressive brain atrophy, but no obvious neuronal loss. Neuronal abnormalities are associated with massive NIIs. Abnormalities in individual neurons including reductions in the number and size of spines as well as in the area of perikarya and diameter of dendrites were also observed. These abnormalities probably explain the brain atrophy and neuronal dysfunction in this disease [Sakai et al 2006, Sato et al 2009, Suzuki et al 2012, Suzuki et al 2013].
Recently lysine-specific demethylase 1 (LSD1) and its target ATN1 were shown to be responsible for neuronal progenitor cell maintenance during cortical development in vivo [Zhang et al 2014].
Gene structure.
ATN1 comprises ten exons spanning 20 kb; it is alternatively spliced resulting in two transcript variants (NM_001007026.1 and NM_001940.3) that encode the same protein with differences only in their untranslated exons (NP_001007027.1 and NP_001931.2). For a detailed summary of gene and protein information, see Table A, Gene.
Benign variants. The CAG repeat in ATN1 is located in exon 5, 1,462 bp downstream from the putative methionine initiation codon, and is predicted to code for a polyglutamine stretch. The CAG repeats in normal individuals range from six to 35 repeat units [Koide et al 1994, Nagafuchi et al 1994, Ikeuchi et al 1995a, Ikeuchi et al 1995c].
Mutable normal alleles. Mutable normal alleles may exist; Takano et al [1998] have shown that the normal Japanese population has a greater number of individuals with 20-35 CAG repeats than are found in populations of European origin. Mutable normal alleles are not associated with symptoms but are hypothetically unstable and could expand on transmission resulting in occurrence of symptoms in the next generation. However, no case of a mutable allele expanding or contracting in the subsequent generation has been reported.
Pathogenic variants. The CAG repeats in individuals with DRPLA range from 48 to 93 repeat units [Koide et al 1994, Nagafuchi et al 1994, Ikeuchi et al 1995a, Ikeuchi et al 1995b, Ikeuchi et al 1995c, Alford et al 1997, Shimojo et al 2001] (for more information, see Table A).
Table 3.
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Variant Classification | DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
Benign
| c.1462CAG(6_35) (CAG 6-35 repeats) | See footnote 1. |
NM_001007026.1
NP_001007027.1
|
Pathogenic
| c.1462CAG(49_55) 2 | See footnote 2. |
c.1462CAG(48_93) (CAG 48-93 repeats) | See footnote 1. |
c.1462CAG(90_93) 3 (CAG 90-93 repeats) | See footnote 1. |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Each CAG repeat results in the addition of a glutamine residue to the polymorphic polyglutamine repeat.
- 2.
- 3.
Normal gene product. The ATN1 cDNA is predicted to code for 1,190 amino acids. Atrophin-1 is a nuclear protein with putative nuclear localizing signals [Sato et al 1999a, Nucifora et al 2003]. Several studies have suggested that the Drosophila ortholog of atrophin-1 (DRPLA protein) functions as a transcriptional co-regulator in diverse developmental processes [Wood et al 2000, Zhang et al 2002, Charroux et al 2006, Shen et al 2007].
Abnormal gene product. Expression of truncated proteins encoded by ATN1 with expanded polyglutamine stretches result in frequent formation of peri- and intranuclear aggregates and apoptotic cell death, suggesting that processed expanded proteins are more toxic to cells than full-length proteins [Igarashi et al 1998, Shimohata et al 2002]. Expanded polyglutamine stretches have been shown to interact with TATA-binding protein (TBP)-associated factors (TAFII130) or cAMP response element-binding protein (CREB)-binding protein (CBP), resulting in the suppression of CREB-dependent transcriptional activation that is vital for neuronal survival and plasticity [Shimohata et al 2000, Nucifora et al 2001, Shimohata et al 2005].