Adolescent; Adult; Amino Acid Transport Systems, Acidic; Antiporters; Atrophy; Basal Ganglia; Cell Line, Tumor; Cerebellum; Child; Child, Preschool; DNA Mutational Analysis; Family Health; Female; HeLa Cells; Hereditary Central Nervous System Demyelinating Diseases; Humans; Image Processing, Computer-Assisted; Italy; Magnetic Resonance Imaging; Male; Mitochondrial Diseases; Polymorphism, Single Nucleotide; Proteins; Psychomotor Disorders; Transfection; Tubulin; Young Adult
OBJECTIVE: To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations.
METHODS: We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening. We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression.
RESULTS: Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy. The majority of patients had a known Roma ethnic background. Single nucleotide polymorphism array analysis in 5 patients identified one large overlapping homozygous region on chromosome 13. WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1. Sanger sequencing confirmed homozygosity for this variant in all 16 patients. All patients shared a common haplotype, indicative of a founder effect. Screening of 1,000 controls from different European Roma panels demonstrated an overall carrier rate of the mutation of 3%-25%. Transfection assays showed that the deletion significantly reduced expression in specific CNS cell lines.
CONCLUSIONS: UFM1 encodes ubiquitin-fold modifier 1 (UFM1), a member of the ubiquitin-like family involved in posttranslational modification of proteins. Its exact biological role is unclear. This study associates a UFM1 gene defect with a disease and sheds new light on possible UFM1 functional networks.
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Hamilton, E., Bertini, E., Kalaydjieva, L., Morar, B., Dojčáková, D., Vanderver, A., & Recessive H-ABC Research Group. (2017). UFM1 founder mutation in the Roma population causes recessive variant of H-ABC.. Neurology, 89 (17). http://dx.doi.org/10.1212/WNL.0000000000004578