Molecular characteristics
ALKBH8 (AlkB homolog 8) gene is located at 11q22.3 and encodes an atypical member of the AlkB family of dioxygenases which is responsible for the formation of 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U), 5-methoxycarbonylhydroxymethyluridine ([S]-mchm5U) and (R)-mchm5U, 5-methoxycarbonylmethyluridine (mcm5U), and 5-methoxycarbonylmethyl-2’-O-methyluridine (mcm5Um) at the anticodon wobble uridines of specific tRNAs. These modifications are likely critical for circumventing the lack of a specific anti-codon for selenocysteine in mammals. Selenocysteine is known to be found in 25 proteins, including glutathione peroxidases and thioredoxin reductases which are essential for the detoxification of reactive oxygen species.
Mutations and pathophysiology
Homozygous pathogenic truncating variants in ALKBH8 have been reported in 7 individuals from 2 unrelated multiplex consanguineous Saudi families with MRT71.
The following are selected cases from the 2 families with ALKBH8 pathogenic variants as reported by Monies et al. (2019):
- Index individual from family 1 is a 12-year-old boy with homozygosity for c.1660C>T variant in ALKBH8 (NM_001301010.1) leading to a p.Arg554* presented with intellectual disability, global developmental delay, epilepsy, hyperactivity, poor attention span, small penis, cryptorchidism, and mild dysmorphism in the form of an overbite.
- Index individual from family 2 is a 16-year-old boy with homozygosity for c.1794delC (p.Trp599Glyfs*19) presented with intellectual disability, global developmental delay, epilepsy, attention deficit hyperactivity disorder, and congenital heart disease in the form of ventricular septal defect and thickened aortic valve.