Biallelic germline variants (either homozygous or compound heterozygous) in UGDH gene cause Jamuar syndrome. The variants reported are distributed throughout the gene and include missense and nonsense variants (figure 1 below). However, none of the reported patients carried biallelic nonsense mutations, suggesting that biallelic LOF variants in UGDH gene may be embryonically lethal in humans. In addition, there was a common homozygous pathogenic variant (p.Arg317Gln) identified in 9 individuals from 4 unrelated Saudi Arabian families. These individuals were identified by exome sequencing across multiple laboratories.
Figure 1: UGDH genomic and protein domain structures: Types positions of mutations reported in Jamuar syndrome. (Source: Hengel et al. PMID: 32175296).
UGDH gene codes for an enzyme that converts UDP-glucose to UDP-glucuronic acid, an obligate precursor for the synthesis of proteoglycans of the extracellular matrix, through reduction of NAD+ into NADH. The UGDH protein consists of three distinct domains: the NAD-binding (N-terminal) and UDP-binding (C-terminal) domains, and an internal domain that bridges the two termini together. The enzyme assembles into a disc-shaped double layer composed of a trimer of dimers to form a hexameric complex. Mutations in the NAD-binding domain are expected to impair NAD+ reduction, while mutations in the central domain are expected to affect homo-dimerization, and mutations in the UDP-binding domain may prevent UGDH from assembling into a functional hexameric enzyme.
Fibroblasts derived from 3 unrelated patients showed decreased UGDH protein levels compared to controls. In addition, there was decreased UGDH-catalyzed reduction of NAD+ to NADH. Finally, cerebral organoids generated from iPSCs of 3 patients showed decreased volume and impaired expression of proteins associated with neuronal progenitors compared to controls. In summary, the genetic, biochemical and cellular findings reveal that these UGDH germline variants behave as loss-of-function alleles.