Document Type

Journal Article

Publication Date








Inclusive Pages





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.


Reproduced with permission of the American Academy of Neurology. Neurology

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Peer Reviewed


Open Access