UFM1 founder mutation in the Roma population causes recessive variant of H-ABC

• Published in: Neurology Vol. 89; no. 17; p. 1821
• Main Authors: Hamilton, Eline M C, Bertini, Enrico, Kalaydjieva, Luba, Morar, Bharti, Dojčáková, Dana, Liu, Judy, Vanderver, Adeline, Curiel, Julian, Persoon, Claudia M, Diodato, Daria, Pinelli, Lorenzo, van der Meij, Nathalie L, Plecko, Barbara, Blaser, Susan, Wolf, Nicole I, Waisfisz, Quinten, Abbink, Truus E M, van der Knaap, Marjo S
• Format: Journal Article
• Language: English
• Published: United States 24.10.2017
• Subjects: Adolescent; Adult; Amino Acid Transport Systems, Acidic - deficiency; Amino Acid Transport Systems, Acidic - genetics; Antiporters - deficiency; Antiporters - genetics; Atrophy - etiology; Basal Ganglia - diagnostic imaging; Basal Ganglia - pathology; Cell Line, Tumor - pathology; Cerebellum - diagnostic imaging; Cerebellum - pathology; Child; Child, Preschool; DNA Mutational Analysis; Family Health; Female; HeLa Cells; Hereditary Central Nervous System Demyelinating Diseases - complications; Hereditary Central Nervous System Demyelinating Diseases - diagnostic imaging; Hereditary Central Nervous System Demyelinating Diseases - genetics; Humans; Image Processing, Computer-Assisted; Italy; Magnetic Resonance Imaging; Male; Mitochondrial Diseases - complications; Mitochondrial Diseases - diagnostic imaging; Mitochondrial Diseases - genetics; Polymorphism, Single Nucleotide - genetics; Proteins - genetics; Psychomotor Disorders - complications; Psychomotor Disorders - diagnostic imaging; Psychomotor Disorders - genetics; Transfection; Tubulin - genetics; Young Adult
• ISSN: 1526-632X
• DOI: 10.1212/WNL.0000000000004578

To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for mutations. 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. 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 . 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. 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 gene defect with a disease and sheds new light on possible UFM1 functional networks.