Relevance to Autism

Fanjul-Fernandez et al., 2021 studied a large multi-generational family of European ancestry with multiple family members affected with ASD or the broader autism phenotype (BAP) and identified a rare heterozygous missense variant in the GBE1 gene (NM_000158.4:c.176T>C;p.Ile59Thr) that was present in seven of seven individuals with ASD, nine of ten individuals with the BAP and none of the four tested unaffected individuals. Furthermore, subsequent genotyping of a community-acquired cohort of 389 individuals with ASD in this report identified three additional probands with the p.Ile59Thr missense variant in GBE1; cascade analysis demonstrated that this variant was present in eleven of thirteen individuals with familial ASD/BAP and neither of the two tested unaffected individuals in these three families, also of European ancestry. Functional analysis of the p.Ile59Thr variant demonstrated a decrease in steady state levels of mutant protein in transiently transfected cells compared to wild-type protein. Lastly, this report demonstrated while the GBE1 variant was not enriched in the combined UK10K ASD cohorts of European ancestry (16/604 ASD cases vs. 189/7935 European controls, OR 1.11, P = 0.68), heterozygous GBE1 deletions were overrepresented in a cohort of cases with ASD and other neurodevelopmental disorders (6 deletions in 29,085 cases vs. none in controls; p = 0.045), as well as in a cohort of ASD cases from the Autism Genome Project (11 deletions in 7,745 cases vs. one in 21,694 alleles in gnomAD). Inherited nonsense variants in the GBE1 gene had previously been identified in ASD probands from the iHART cohort in Ruzzo et al., 2019.

Molecular Function

The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease).

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