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

Abstract

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.

Ribosomal protein RPL26 is the principal target of UFMylation

“…ECM proteins, particularly collagens, require an extensive set of specialized factors to fold, modify, assemble, secrete, process, and cross-link these large, rigid molecules (42). The robust association of human UFMylation genes with abnormal brain development and microcephaly in humans (3,11,23,43) and with defective neuromuscular junction formation in Drosophila (12) suggests a role for UFMylation in tissue development, a process that is intimately dependent on cell-cell and cell-matrix interaction. In this regard, it is especially noteworthy that rare allelic variants of DDRGK1 (13) and UFSP2 (14,15) are linked to human skeletal dysplasias affecting cartilage development and that DDRGK1 deficiency is associated with impaired cartilage development in zebrafish and with delayed chondrogenesis in the mouse (13).…”

“…ubiquitin-like protein modifier (UBL) that is ubiquitously expressed in metazoans but absent from fungi (1) and is essential for brain and hematopoietic development (2)(3)(4). Like ubiquitin and other UBLs, UFM1 is covalently ligated to lysine residues on target proteins by a three-step cascade catalyzed by E1, E2, and E3 enzymes, encoded by UBA5, UFC1, and UFL1 genes, respectively (1, 5) ( Fig.…”

The UFM1 cascade times mitosis entry associated with microcephaly

“…17,18,20,26,27 However, the mechanism behind its contribution to microcephaly remains to be defined. 17,18,20,26,27 However, the mechanism behind its contribution to microcephaly remains to be defined.…”

“…17 Later, several studies discovered biallelic variants of UBA5 in children with microcephaly, intellectual disability, movement disorders, and severe dystonia. 26,27 These studies collectively highlight the indispensable role of the UFM1 cascade in the development of the brain and link it closely to microcephaly. 26,27 These studies collectively highlight the indispensable role of the UFM1 cascade in the development of the brain and link it closely to microcephaly.…”

Ubiquitin fold modifier 1 activates NF-κB pathway by down-regulating LZAP expression in the macrophage of diabetic mouse model

“…The construction of UFM1 promoter reporters was performed as described previously [24]. Briefly, the wild-type and mutant UFM1promoter (c.-1889 to c.-1 of NM 001286704.1) were cloned into the pNL1.1 reporter (Promega, Madison, WI, U.S.A.) using the infusion protocol (Clontech, Mountain View, CA).…”