Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts

Abstract

BackgroundMutations in the gene STUB1, encoding the protein CHIP (C-terminus of HSC70-interacting protein), have recently been suggested as a cause of recessive ataxia based on the findings in few Chinese families. Here we aimed to investigate the phenotypic and genotypic spectrum of STUB1 mutations, and to assess their frequency in different Caucasian disease cohorts.Methods300 subjects with degenerative ataxia (n = 167) or spastic paraplegia (n = 133) were screened for STUB1 variants by whole-exome-sequencing (n = 204) or shotgun-fragment-library-sequencing (n = 96). To control for the specificity of STUB1 variants, we screened an additional 1707 exomes from 891 index families with other neurological diseases.ResultsWe identified 3 ataxia patients (3/167 = 1.8%) with 4 novel missense mutations in STUB1, including 3 mutations in its tetratricopeptide-repeat domain. All patients showed evidence of pyramidal tract damage. Cognitive impairment was present only in one and hypogonadism in none of them. Ataxia did not start before age 48 years in one subject. No recessive STUB1 variants were identified in families with other neurological diseases, demonstrating that STUB1 variants are not simply rare polymorphisms ubiquitous in neurodegenerative disease.ConclusionsSTUB1-disease occurs also in Caucasian ataxia populations (1.8%). Our results expand the genotypic spectrum of STUB1-disease, showing that pathogenic mutations affect also the tetratricopeptide-repeat domain, thus providing clinical evidence for the functional importance of this domain. Moreover, they further delineate the phenotypic core features of STUB1-ataxia. Pyramidal tract damage is a common accompanying feature and can include lower limb spasticity, thus adding STUB1-ataxia to the differential diagnosis of “spastic ataxias”. However, STUB1 is rare in subjects with predominant spastic paraplegia (0/133). In contrast to previous reports, STUB1-ataxia can start even above age 40 years, and neither hypogonadism nor prominent cognitive impairment are obligatory features.

Regulation of autophagic flux by CHIP

“…CHIP plays a crucial role in cytoplasmic homeostasis and cell viability by decreasing or stabilizing its substrates [11,12] . It participates in a number of biological processes, especially in neurodegeneration including AD, PD, HD, ALS, and several types of ataxia [12,13,[24][25][26][27][28] . Here, we showed that the clearance occurs frequently in neurodegenerative diseases [3,4] .…”

“…Thus, CHIP has protective effects against the toxicity of neurodegenerative disease proteins. Recently, loss-of-function mutations in CHIP were identified as a causative genetic factor for a group of autosomal recessive cerebellar ataxias [24][25][26][27][28] . However, the precise mechanism of the involvement of CHIP in neurodegeneration remains unclear.…”

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

“…Biallelic STUB1 mutations were first published as a cause of recessive ataxia (eg, as part of a Gordon Holmes syndrome). 26,27 Later studies then revealed that corticospinal tract damage is a frequent concomitant feature 28 and sometimes even is predominate in the clinical presentation. 29 Examples can also be found for recently identified autosomal-dominant disease genes.…”

Moving Beyond Syndromic Classifications in Neurodegenerative Disease: The Example of PLA2G6

“…The Boucher‐Neuhäuser and Gordon‐Holmes syndromes are caused by patatin‐like phospholipase domain containing 6 ( PNPLA6 ) mutations not in isolation, but as part of wide spectrum of ataxia and hereditary spastic paraplegia (HSP) presentations ( Orphanet Journal of Rare Diseases , under review) . The Gordon‐Holmes syndrome can also be caused by STIP1 homology and U‐box containing protein 1 ( STUB1 ) mutations, here again as part of continuous spectrum of ataxia disease with variably combined disease features ( Orphanet Journal of Rare Diseases , under review) X‐linked Charcot‐Marie‐Tooth disease type 5 (CMTX5), Arts syndrome, and nonsyndromic sensorineural deafness (DFN2) are continuous allelic phenotypic clusters caused by phosphoribosyl pyrophosphate synthetase 1 ( PRPS1 ) mutations …”