Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Epileptic encephalopathies are severe childhood epilepsies with diverse genetic causes.
• Next-generation sequencing has revealed numerous genes implicated in these conditions, including UBA5.
• UBA5 is crucial for ufmylation, a post-translational modification pathway, and is the first ufmylation gene linked to disease.

Observation:

• Genome sequencing of two sisters with early-onset epileptic encephalopathy revealed compound heterozygous mutations in the UBA5 gene.
• One sister inherited a splice-site mutation (c.684G > A) causing loss-of-function, while the other inherited a missense mutation (p.Ala371Thr) previously associated with pathogenicity.
• Three adult Icelanders homozygous for the p.Ala371Thr mutation showed no neurological symptoms, suggesting it is a hypomorphic allele.

Findings:

• The identified compound heterozygous UBA5 mutations in the sisters are novel and not found in large reference populations.
• The splice-site mutation leads to loss-of-function of one UBA5 allele.
• The p.Ala371Thr mutation appears to be hypomorphic, as individuals homozygous for it exhibit no disease phenotype.

Implications:

• This research provides the first description of UBA5 mutations since their initial discovery in 2016.
• It confirms the hypomorphic nature of the p.Ala371Thr variant.
• The findings contribute to understanding the genetic basis of epileptic encephalopathies and the role of the ufmylation pathway in neurological disorders.