Molecular characteristics

Molecular Characteristics
UFM1 (Ubiquitin-Fold Modifier 1) encodes for a ubiquitin-like protein that is conjugated to target proteins via the action of E1 activating enzymes (UBA5), E2 conjugating enzymes (UFC1) and an E3 ligase (UFL1) in a process called ufmylation. The process begins with the activation of UFM1 by UBA5 with the formation of a thioester bond. UFC1 then accepts UFM1 and forms an intermediate with UFM1 by a similar thioester linkage. Lastly, UFM1 is transferred to the substrate protein through UFL1 enzyme. Ufmylation is notably involved in reticulopahgy in response to endoplasmic reticulum stress. The gene has low regional specificity and is expressed in most tissues.

Mutations and pathophysiology
Dysfunction at one of levels of the ufmylation process (UFM1 mutations, UFC1 mutations, UBA5 mutations) have been shown to lead to neurodevelopmental defects. Mouse knock-out models of UFM1 resulted in death within the first day of life, with post-mortem examination revealing microcephaly and neuronal apoptosis. In humans, UFM1 pathogenic variants have are linked to hypomyelinating leukodystrophy-14.

Nahorski et al. (2018) reported a homozygous truncating variants in UFM1 (NM_001286704.1) c.241C4T:p.(Arg81Cys) in 4 patients from 2 Sudani families.
Hamilton et al. (2017) reported a homozygous 3 base-pair deletion (c.-273_-271delTCA) (NM_001286704.1) founder mutation in 16 patients from 12 families of Roma descent.