In 6 patients from a consanguineous Bedouin family (AH) with syndromic thrombocytopenia-13 (THC13; 620776), Seo et al. (2019) identified a homozygous c.151C-T transition (c.151C-T, NM_001127621) in the GALE gene, resulting in an arg51-to-trp (R51W) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies of patient cells were not performed. In vitro functional expression studies showed that the R51W protein had about 40% residual activity for both interconversion functions compared to wildtype and showed reduced NAD+ binding (41% reduction compared to wildtype). Of note, the mutant protein was able to rescue yeast growth upon galactose challenge in gal10-null yeast (gal10 is the homologous gene to GALE and catalyzes the interconversion of UDP-galactose and UDP-glucose, but not the interconversion of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine). Accordingly, the patients did not have clinical signs of galactosemia. The melting point of the R51W mutant was lower than controls, indicating thermal instability. The authors postulated that deficiency of glycosylation resulting from decreased levels of GALE due to thermal instability may have a detrimental effect on normal glycosylation and hematopoiesis.
For discussion of the R51W mutation in the GALE gene that was found in compound heterozygous state in a 2-year-old Hispanic boy with THC13 by Febres-Aldana et al. (2020), see 606953.0010.
