A gene, underlying a severe, infantile-onset encephalopathy enriched in Europeans, identified by Lehesjoki Group

In an international collaborative study, the Lehesjoki Group identified a new severe infantile-onset encephalopathy that is caused by autosomal recessively inherited mutations in the UBA5 gene. The study established UBA5, which had not previously been linked to human disease, as a critical component for central nervous system development. The study highlighted the importance of international collaboration and data sharing between research groups and clinical genetic laboratories in facilitating advances in genetic research of rare diseases.

Utilizing whole-exome sequencing, compound heterozygous variants in UBA5 were initially identified in two Finnish families that were part of a larger study aiming to characterize disease-causing mutations in a cohort of Finnish individuals with severe epileptic syndromes. One additional case with UBA5 mutations was identified in Northern Finland Intellectual Disability Cohort and two further cases from the large UK-based Deciphering Developmental Disorders study. Patients in all five families have a p.Ala371Thr missense variant in one allele, and it is coupled with a more severe variant in the other allele. The p.Ala371Thr is relatively common in Finns and Europeans. It is, therefore, expected that the disease is enriched in Finns and Europeans. Indeed, in a parallel German-French collaborative study, published in the same issue of the American Journal of Human Genetics, two further families with this mutation were described.

Functional studies to assess the molecular mechanism of UBA5 dysfunction, conducted in collaboration with Prof. Masaaki Komatsu’s Group from Niigata University in Japan, showed that the identified UBA5 variants cause reduced but not completely abolished enzymatic activity of UBA5, which together with the observed embryonic lethality in Uba5 knockout mouse, indicates that complete loss of function of UBA5 is not compatible with life. The UBA5 protein is an activating enzyme for UFM1, which is a small ubiquitin-like protein that is conjugated to its target proteins. The function of the UFM1 conjugation is still largely unknown but it has been suggested to be involved in the so called unfolded or misfolded protein response. Symptoms of the UBA5 patients and findings in the central nervous system specific knockout mice for Ufm1 together indicate that the UFM1-cascade (see figure) is essential for normal development and function of the central nervous system.


Original study:

Muona M, Ishimura R, Laari A, Ichimura Y, Linnankivi T, Keski-Filppula R, Herva R, Rantala H, Paetau A, Pöyhönen M, Obata M, Uemura T, Karhu T, Bizen N, Takebayashi H, McKee S, Parker MJ, Akawi N, McRae J, Hurles ME; DDD Study, Kuismin O, Kurki MI, Anttonen AK, Tanaka K, Palotie A, Waguri S, Lehesjoki AE, Komatsu M. Biallelic variants in UBA5 link dysfunctional UFM1 ubiquitin-like modifier to severe infantile-onset encephalopathy. Am J Hum Genet 99: 683-694, 2016