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

作者：Hamilton, Eline M. C.; Bertini, Enrico; Kalaydjieva, Luba; Morar, Bharti; Dojcakova, 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.^*

来源：Neurology, 2017, 89(17): 1821-1828.

DOI：10.1212/WNL.0000000000004578

• BASAL GANGLIA
• BIALLELIC VARIANTS
• HYPOMYELINATION
• ATROPHY
• DOMAIN
• CEREBELLUM
• NEUROPATHY
• SYSTEM

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.

• 出版日期2017-10-24
• 单位河北医科大学