Disease-associated polyalanine expansion mutations impair UBA6-dependent ubiquitination.

Expansion mutations in polyalanine stretches are associated with a growing number of diseases sharing a high degree of genotypic and phenotypic commonality. These similarities prompted us to query the normal function of physiological polyalanine stretches and to investigate whether a common molecular mechanism is involved in these diseases. Here, we show that UBA6, an E1 ubiquitin-activating enzyme, recognizes a polyalanine stretch within its cognate E2 ubiquitin-conjugating enzyme USE1. Aberrations in this polyalanine stretch reduce ubiquitin transfer to USE1 and, subsequently, polyubiquitination and degradation of its target, the ubiquitin ligase E6AP. Furthermore, we identify competition for the UBA6-USE1 interaction by various proteins with polyalanine expansion mutations in the disease state. The deleterious interactions of expanded polyalanine tract proteins with UBA6 in mouse primary neurons alter the levels and ubiquitination-dependent degradation of E6AP, which in turn affects the levels of the synaptic protein Arc. These effects are also observed in induced pluripotent stem cell-derived autonomic neurons from patients with polyalanine expansion mutations, where UBA6 overexpression increases neuronal resilience to cell death. Our results suggest a shared mechanism for such mutations that may contribute to the congenital malformations seen in polyalanine tract diseases.

The phenotype of homozygous EMC10 variant: A new syndrome with intellectual disability and language impairment.

AIM: To explore the cognitive and behavioral phenotype associated with a recently reported variant in endoplasmic reticulum membrane complex EMC10 c.287delG (Gly96Alafs∗9), suggested to cause a novel syndromic neurodevelopmental disorder. METHODS: Homozygous EMC10 variant identified by a combination of autozygosity mapping and exome sequencing was found in five children (aged 7-18) from a large extended family. Their functioning was compared to normative data as well as to that of age-matched relatives (siblings/cousins), sharing similar familial and demographic characteristics. Neuropsychological, behavioral, and daily functioning were assessed. RESULTS: Performance of all participants with EMC10 variant on both cognitive functioning and adaptive skills was lower than the normal range fulfilling diagnostic criteria for intellectual disability. Their functioning was also lower than that of their matched relatives on most areas of functioning, except visual memory that was found higher, in the low average range. Language difficulty was apparent in all participants with EMC10, and a discrepancy within participants' phenotype was found, with lower verbal abilities compared to visuospatial ability. More behavioral problems were found, although not in all participants with EMC10. CONCLUSION: Homozygous EMC10 variant was found associated with a phenotype of intellectual disability and language deficits.