Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary

Abstract

Ufmylation is a relatively newly discovered type of post-translational modification when the ubiquitin-fold modifier 1 (UFM1) protein is covalently attached to its target proteins in a three-step enzymatic reaction involving an E1 activating enzyme (UBA5), E2 conjugating enzyme (UFC1), and E3 ligase enzyme (UFL1). The process of ufmylation is essential for normal brain development and function in humans. Mutations in the UFM1 gene are associated with Hypomyelinating leukodystrophy type 14, presenting with global developmental delay, failure to thrive, progressive microcephaly, refractive epilepsy, and hypomyelination, with atrophy of the basal ganglia and cerebellum phenotypes. The c.-155_-153delTCA deletion in the promoter region of UFM1 is considered to be a founding mutation in the Roma population. Here we present four index patients with homozygous UFM1:c.-155_-153delTCA mutation detected by next-generation sequencing (whole genome/exome sequencing) or Sanger sequencing. This mutation may be more common in the Roma population than previously estimated, and the targeted testing of the UFM1:c.-155_-153delTCA mutation may have an indication in cases of hypomyelination and neurodegenerative clinical course in pediatric patients of Roma descent.

Severe Epilepsy and Movement Disorder May Be Early Symptoms of TMEM106B -Related Hypomyelinating Leukodystrophy

“…Our report underscores that early-onset severe epilepsy may be among the major symptoms of HLD. As already suggested in other rare forms of HLD ( ARV1 and UFM1 -related HLD 7 , 8 ), we think that TMEM106B -HLD should be included in the differential diagnosis of genetic early-onset encephalopathies with epilepsy.…”

A guide to UFMylation, an emerging posttranslational modification

“…Therefore, an important function of UFSPs is the generation of a free pool of mature UFM1 through proteolysis of the UFM1 precursor. This involves the removal of a serine 84 -cysteine 85 di-peptide to expose the C-terminal glycine of UFM1 that is required for conjugation to substrates [28]. Until recently, UFSP1 was thought to be catalytically inactive in humans due to its mistaken annotation as an 'Inactive UFM1 specific protease'.…”

The UFM1 conjugation system in mammalian development

“…This UFM1 mutation significantly diminishes the formation of UFM1‐UBA5 and UFM1‐UFC1 intermediates, which results in impaired protein UFMylation 55 . Additionally, a mutation in the promoter region of UFM1 is present in a diverse population of patients with hypomyelination and atrophy of the basal ganglia and cerebellum 56‐58 . The deletion of the UFM1 promoter reduces the UFM1 activity in neuroblastoma and astroglioma cell lines 58 .…”

“…55 Additionally, a mutation in the promoter region of UFM1 is present in a diverse population of patients with hypomyelination and atrophy of the basal ganglia and cerebellum. [56][57][58] The deletion of the UFM1 promoter reduces the UFM1 activity in neuroblastoma and astroglioma cell lines. 58 Multiple UBA5 variants are found in patients with neurodevelopment disorders, including autosomal recessive cerebellar ataxia, hypomyelination with atrophy, early-onset encephalopathy, and early myoclonic epilepsy.…”