Curation SCA7 ATXN7

GeneReviews summarizes SCA7 as established by identification of a heterozygous abnormal ATXN7 CAG trinucleotide repeat expansion in a proband and notes that more than 1,000 affected individuals have been identified worldwide.

GeneReviews defines ATXN7 CAG repeat ranges as normal 7–27, mutable normal 28–33, pathogenic reduced penetrance 34–36, and pathogenic full penetrance 37–460 repeats; longer repeats correlate with earlier onset, greater severity, and faster progression.

In 8 SCA7 families, RED detected 150-240 bp CAG expansion products in all affected individuals; expansions cosegregated with disease (P < 0.000001, n = 66), with repeat-size instability observed in affected offspring.

Uploaded case-control/cohort studies support ATXN7 CAG expansion enrichment in SCA7: Chinese families showed affected alleles of 44-85 CAG versus 9-18 in 67 controls; Indian SCA7 families had 22 affected individuals with 40-94 CAG expansions and 382 population controls; rs6798742 haplotype association was replicated in Indian and Mexican expansion carriers. PMID 30721448 is a biomarker case-control study, not primary expansion-enrichment evidence.

Gene-level/locus-relevant evidence: ataxin-7 is a core STAGA/TFTC transcription co-activator component with histone acetyltransferase-related function; polyQ expansion alters this activity.

Gene-level/locus-relevant evidence: ataxin-7 is incorporated into STAGA/TFTC transcription co-activator complexes and mutant polyQ-expanded ataxin-7 perturbs interactions with transcriptional regulatory machinery.

PolyQ-expanded ataxin-7 alters SAGA/STAGA/TFTC histone acetyltransferase activity and chromatin/transcriptional regulation in disease-relevant experimental systems.

Patient CNS tissue shows mutant ataxin-7 nuclear inclusions with ubiquitin-proteasome components and neurodegenerative pathology in SCA7-vulnerable regions; evidence is tissue/cell-level but not a separate locus-genotyping cohort.

Non-patient cell models expressing mutant polyQ-expanded ataxin-7 show enhanced nuclear localization/toxicity and activation of apoptotic pathways, supporting a repeat-length-dependent toxic gain of function.

SCA7 mouse models expressing polyQ-expanded ataxin-7 develop gait ataxia, nuclear inclusions, Purkinje-cell dendritic degeneration, and non-cell-autonomous cerebellar pathology resembling human SCA7.

Cell-culture models expressing polyQ-expanded ataxin-7 reproduce disease-relevant molecular phenotypes, including altered transcriptional regulation, mutant protein accumulation, and cellular toxicity.