Heterozygous Deletion of KLHL1/ATX8OS at the SCA8 Locus Is Unlikely Associated With Cerebellar Impairment in Humans

Abstract

Spinocerebellar ataxia type 8 (SCA8) (MIM 608768) is a dominantly inherited ataxia typically occurring in adulthood, with onset of the disease that may range from age 1 to 65 years [1–6]. Common initial symptoms are scanning dysarthria with a characteristic drawn-out slowness of speech and gait instability. Some individuals present with nystagmus, dysmetric saccades and, occasionally ophthalmoplegia. Hyperreflexia and extensor plantar responses are present in some severely affected individuals. Life span is typically not shortened. SCA8 is caused by repeat expansions initially thought to involve a non-coding CTG tract in the ATXN8OS gene— formerly known as SCA8 (MIM 603680)—an untranslated antisense transcript partially overlapping the Kelch-like 1 gene (KLHL1) (MIM 605332) [7]. The CTG repeat was later found to be transcribed also in the opposite direction as (CAG)n repeat in the ATXN8 gene, encoding a nearly pure polyglutamine protein [8]. An RNA toxic effect of the CUG expanded repeats has been suggested, together with the possibility of non-ATG translation (RAN translation) which occurs across long, hairpin-forming repeats and results in the accumulation of potentially toxic SCA8 polyalanine [9, 10]. The (CTG.CAG)n repeat length most often associated with ataxia ranges from 80 to 250. However, repeats from 71 to more than 1300 have been occasionally found in individuals with ataxia. The disease is characterized by a reduced penetrance most often with alleles of fewer than 100 repeats. We report two unrelated families with genomic deletions completely overlapping ATXN8OS gene and great part of KLHL1 gene. These deletions were present in a healthy parent in both families. A total of four subjects with ATXN8OS/ KLHL1 genes deletion could be studied and did not show any cerebellar symptoms or MRI changes in cerebellum.