A Missense Mutation in the UGDH Gene Is Associated With Developmental Delay and Axial Hypotonia

Abstract

UDP-glucose dehydrogenase (UGDH) encodes an oxidoreductase that converts two successive oxidations of UDP-glucose to produce UDP-glucuronic acid, a key component in the synthesis of several polysaccharides such as glycosaminoglycan and the disaccharide hyaluronic acid. UGDH is critical to the production of extracellular matrix components which are essential to the migration and connectivity of neurons early in human brain development. In this report, we describe one child of a consanguineous family who presented with distinct clinical features including global developmental delay, axial hypotonia, bilateral undescended testis, and subtle dysmorphic features. Whole genome sequencing and a segregation was performed to identify the genetic cause of the disease within the family. Though mutations in the UGDH protein have been described as causing developmental delay in various model organisms, to our knowledge, this is the first identification of the novel homozygous missense variant in exon8 of UGDH NM_003359.3: c.950 G>A (p.Arg317Gln) and most likely the cause of the patient's phenotype. This variant falls in an active region and replaces the highly conserved Arginine 317 residues across mammals.

A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism

“…In humans and model organisms, UGDH mutants have led to various alternate developmental outcomes. One example, is a homozygous missense variant, NM_003359.4( UDGH ):c.950G>A (p.Arg317Gln), which was observed in humans as a causative variant for a patient experiencing a range of distinct clinical features including global developmental delay, axial hypotonia, bilateral undescended testis, and subtle dysmorphic features [ 80 ]. The mutation was located in exon 8 and belongs to the same exon 8 region in cats that appeared to be duplicated as part of the feline dwarfism SV, a region of the protein known as the central domain.…”

Skeletal Manifestations of Heritable Disproportionate Dwarfism in Cats as Determined by Radiography and Magnetic Resonance Imaging

“…The UGDH gene encodes an oxidoreductase enzyme that converts UDP-glucose to UDP-glucuronic acid. 34 UDP-glucuronic acid is an essential sugar nucleotide which serves as a precursor and regulator of several sulphated glycosaminoglycans. 35 Proteoglycans comprised of such glycosaminoglycans are critical to the regulation of many types of growth factors including those in the FGF family.…”

Integration of Sugar Metabolism and Proteoglycan Synthesis by UDP-glucose Dehydrogenase

“…31 A glutamine substitution would remove the positive charge of the guanidinium group, disrupting a critical salt bridge with the negatively charged Glu 460, potentially disrupting the subunit-subunit interface. Although the net outcome is predicted to be similar, the structural interpretations provided in Alhamoudi et al 28 should be viewed with skepticism.…”

“…For example, an arginine substitution at position 317 to a glutamine (R317Q) has been associated with recessive developmental epileptic encephalopathy 29 and developmental delay and axial hypotonia. 28 Arg 317 forms a salt-bridge with Glu 460 and this interaction likely contributes to the positioning of the ID-tail. The helix containing Arg 317 is also immediately upstream of Thr 325, which is critical to efficient hexamer formation.…”

“…19 Additional mechanisms that lead to reduced UGDH expression have been revealed by investigating congenital developmental defects linked to UGDH deficiency. Missense mutations in UGDH that interfere with quaternary assembly of the enzyme result in impaired catalytic activity and reduced stability of UGDH expression, ultimately manifesting in conditions such as cardiac valve malformation, 27 global developmental delay, 28 and epileptic encephalopathy. 29 Lossof-function variants of UGDH in these studies were reported to impair the binding of substrate and cofactor, and/or to disrupt hexameric assembly and stability of the enzyme as discussed in the next section.…”