Heterozygous STUB1 missense variants cause ataxia, cognitive decline, and STUB1 mislocalization

Abstract

ObjectiveTo identify the genetic cause of autosomal dominant ataxia complicated by behavioral abnormalities, cognitive decline, and autism in 2 families and to characterize brain neuropathologic signatures of dominant STUB1-related ataxia and investigate the effects of pathogenic variants on STUB1 localization.MethodsClinical and research-based exome sequencing was used to identify the causative variants for autosomal dominant ataxia in 2 families. Gross and microscopic neuropathologic evaluations were performed on the brains of 4 affected individuals in these families.ResultsMutations in STUB1 have been primarily associated with childhood-onset autosomal recessive ataxia, but here we report heterozygous missense variants in STUB1 (p.Ile53Thr and p.The37Leu) confirming the recent reports of autosomal dominant inheritance. Cerebellar atrophy on imaging and cognitive deficits often preceded ataxia. Unique neuropathologic examination of the 4 brains showed the marked loss of Purkinje cells (PCs) without microscopic evidence of significant pathology outside the cerebellum. The normal pattern of polarized somatodendritic STUB1 protein expression in PCs was lost, resulting in aberrant STUB1 localization in the distal PC dendritic arbors.ConclusionsThis study confirms a dominant inheritance pattern in STUB1-ataxia in addition to a recessive one and documents its association with cognitive and behavioral disability, including autism. In the most extensive analysis of cerebellar pathology in this disease, we demonstrate disruption of STUB1 protein in PCs as part of the underlying pathogenesis.

The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease

“…Despite optimisation within this study, PCR stuttering was observed in the PCR-based assay similar to previous reports 13 , 19 , which is a standard complication when amplifying repetitive genomic sequences, and highlights the need for further optimisation of the assay. By comparison, calling from WGS files revealed a similar distribution as reported previously 33 . While it has been presented as having fewer challenges in optimisation and sequencing, calling of ‘523’ variants was an arduous process and the aforementioned study has stated that the correlation between ‘523’ calling by WGS and PCR-based methods decreases with increasing size of the ‘523’ allele 33 .…”

“…By comparison, calling from WGS files revealed a similar distribution as reported previously 33 . While it has been presented as having fewer challenges in optimisation and sequencing, calling of ‘523’ variants was an arduous process and the aforementioned study has stated that the correlation between ‘523’ calling by WGS and PCR-based methods decreases with increasing size of the ‘523’ allele 33 .…”

“…1. Genotyping of the TOMM40 ‘523’ variant in the PPMI cohort was completed using a WGS method, previously reported as an alternative method to fragment analysis and Sanger sequencing 33 . The distribution of the ‘523’ alleles in PwP compared to healthy controls for both cohorts are presented in Fig.…”

“…Whole genome sequencing (WGS) data were obtained from the PPMI database (available at http://www.ppmi-info.org/data ) in binary alignment map (BAM) format that had been aligned to the human reference genome GRCh38 using the Burrows-Wheeler transform alignment algorithm 31 . Resultant BAM files were analysed using the Integrative Genomics Viewer 32 in order to calculate the length of the poly-T repeat, as previously demonstrated 33 . Alleles were grouped using the convention established by Roses et al 9 : Short (S, T ≤ 19), Long (L, 20 ≤ T ≤ 29) and Very Long (VL, T ≥ 30).…”

CHIP as a therapeutic target for neurological diseases

“…The same phenomena also occurred to SPTBN2, causing both SCA5 and SCAR15 due to dominant and recessive mutations, respectively 120,121 . The researchers named this disease SCA48 119,[122][123][124][125][126] (Fig. 2 and Table 2).…”