Homozygous UBA5 Variant Leads to Hypomyelination with Thalamic Involvement and Axonal Neuropathy

Abstract

The enzyme ubiquitin-like modifier activating enzyme 5 (UBA5) plays an important role in activating ubiquitin-fold modifier 1 (UFM1) and its associated cascade. UFM1 is widely expressed and known to facilitate the post-translational modification of proteins. Variants in UBA5 and UFM1 are involved in neurodevelopmental disorders with early-onset epileptic encephalopathy as a frequently seen disease manifestation. Using whole exome sequencing, we detected a homozygous UBA5 variant (c.895C > T p. [Pro299Ser]) in a patient with severe global developmental delay and epilepsy, the latter from the age of 4 years. Magnetic resonance imaging showed hypomyelination with atrophy and T2 hyperintensity of the thalamus. Histology of the sural nerve showed axonal neuropathy with decreased myelin. Functional analyses confirmed the effect of the Pro299Ser variant on UBA5 protein function, showing 58% residual protein activity. Our findings indicate that the epilepsy currently associated with UBA5 variants may present later in life than previously thought, and that radiological signs include hypomyelination and thalamic involvement. The data also reinforce recently reported associations between UBA5 variants and peripheral neuropathy.

Keywords

UBA5 - UFM1 - hypomyelination - neuropathy

Note

M.S.V.D.K has a patent P112686CA00, therapeutic effects of Guanabenz treatment in vanishing white matter pending to VU University Medical Center. Amsterdam Leukodystrophy Center is a member of the European Reference Network for Rare Neurological Disorders, project ID 739510.

Publication History

Received: 09 August 2020

Accepted: 12 January 2021

Article published online:
14 April 2021

• References

• 1 Daniel J, Liebau E. The UFM1 cascade. Cells 2014; 3 (02) 627-638
• 2 Oweis W, Padala P, Hassouna F. et al. Trans-binding mechanism of ubiquitin-like protein activation revealed by a UBA5-UFM1 complex. Cell Rep 2016; 16 (12) 3113-3120
• 3 Komatsu M, Chiba T, Tatsumi K. et al. A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. EMBO J 2004; 23 (09) 1977-1986
• 4 Azfer A, Niu J, Rogers LM, Adamski FM, Kolattukudy PE. Activation of endoplasmic reticulum stress response during the development of ischemic heart disease. Am J Physiol Heart Circ Physiol 2006; 291 (03) H1411-H1420
• 5 Lemaire K, Moura RF, Granvik M. et al. Ubiquitin fold modifier 1 (UFM1) and its target UFBP1 protect pancreatic beta cells from ER stress-induced apoptosis. PLoS One 2011; 6 (04) e18517
• 6 Arnadottir GA, Jensson BO, Marelsson SE. et al. Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters. BMC Med Genet 2017; 18 (01) 103
• 7 Cabrera-Serrano M, Coote DJ, Azmanov D. et al. A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy. J Med Genet 2020; 57 (12) 835-842
• 8 Colin E, Daniel J, Ziegler A. et al. Biallelic variants of UBA5 reveal that disruption of the UFM1 cascade can result in early-onset encephalopathy. Am J Hum Genet 2018; 26: 86-87
• 9 Daida A, Hamano SI, Ikemoto S. et al. Biallelic loss-of-function UBA5 mutations in a patient with intractable West syndrome and profound failure to thrive. Epileptic Disord 2018; 20 (04) 313-318
• 10 Duan R, Shi Y, Yu L. et al. UBA5 mutations cause a new form of autosomal recessive cerebellar ataxia. PLoS One 2016; 11 (02) e0149039
• 11 Low KJ, Baptista J, Babiker M. et al. Hemizygous UBA5 missense mutation unmasks recessive disorder in a patient with infantile-onset encephalopathy, acquired microcephaly, small cerebellum, movement disorder and severe neurodevelopmental delay. Eur J Med Genet 2019; 62 (02) 97-102
• 12 Mignon-Ravix C, Milh M, Kaiser CS. et al. Abnormal function of the UBA5 protein in a case of early developmental and epileptic encephalopathy with suppression-burst. Hum Mutat 2018; 39 (07) 934-938
• 13 Muona M, Ishimura R, Laari A. et al; DDD Study. Biallelic variants in UBA5 link dysfunctional UFM1 ubiquitin-like modifier pathway to severe infantile-onset encephalopathy. Am J Hum Genet 2016; 99 (03) 683-694
• 14 Nahorski MS, Maddirevula S, Ishimura R. et al. Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development. Brain 2018; 141 (07) 1934-1945
• 15 Hamilton EMC, Bertini E, Kalaydjieva L. et al; Recessive H-ABC Research Group. UFM1 founder mutation in the Roma population causes recessive variant of H-ABC. Neurology 2017; 89 (17) 1821-1828
• 16 Wolf NI, Salomons GS, Rodenburg RJ. et al. Mutations in RARS cause hypomyelination. Ann Neurol 2014; 76 (01) 134-139
• 17 Clos J, Brandau S. pJC20 and pJC40--two high-copy-number vectors for T7 RNA polymerase-dependent expression of recombinant genes in Escherichia coli. Protein Expr Purif 1994; 5 (02) 133-137
• 18 Li Q, Wang K. InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. Am J Hum Genet 2017; 100 (02) 267-280
• 19 Ewans LJ, Schofield D, Shrestha R. et al. Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders. Genet Med 2018; 20 (12) 1564-1574
• 20 Nambot S, Thevenon J, Kuentz P. et al; Orphanomix Physicians' Group. Clinical whole-exome sequencing for the diagnosis of rare disorders with congenital anomalies and/or intellectual disability: substantial interest of prospective annual reanalysis. Genet Med 2018; 20 (06) 645-654
• 21 van der Knaap MS, Bugiani M. Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol 2017; 134 (03) 351-382