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.

Keywords: GDD; Saudi population; UGDH; hypotonia; missense; rare genetic disease.

Figure 1

The index's case presentation and genetics pedigree information. (A) Metabolic mechanism of UDP-glucose dehydrogenase catalysis, UGDH catalyzes two successive oxidations of the UDP-glucose and converts it to UDP-glucuronate, UGDH convert of nicotinamide adenine dinucleotide (NAD) to produce the cofactor nicotinamide adenine dinucleotide phosphate (NADH). UDP-glucuronic acid is an essential sugar nucleotide precursor in the synthesis of polysaccharides, such as Sulfated GAGs and hyaluronic acid. (B) Clinical features of the index with global developmental delay, axial hypotonia, bilateral undescended testis, and subtle dysmorphic features. (C) Family pedigree constructed from the details provided by the index's mother, generated using (https://www.progenygenetics.com), squares (males); circles (females); annotated symbols (affected individuals); open symbols (unaffected individuals); arrowheads (Index). Axial hypotonia; Global developmental delay; dysmorphic features.

Figure 2

Functional annotation of the identified novel homozygous missense variant in UGDH. (A) The chromosomal location of UGDH NM_003359.3 and the position of the identified variant c.950 G>A. Sites of DNaseI hypersensitivity, CHIP-seq defined transcription factor binding regions from multiple independent cell lines; the darkness of the segment is proportional to the signal strength. (B) Segregation analysis containing the phenotype-causing missense c.950 G>A mutation in UGDH for index, index's father (I-1), mother (I-2), both siblings (II-1 and II-3) and a negative control sample.

Figure 3

Predicted effect of R317Q mutation on human UGDH structure and function. (A) Schematic representation of the UGDH (NM_003359.5) genomic region; exons (Blue), intron (Black). Black line represents the identified c.950G>A site mutation. (B) Schematic diagram of the identified variant p.Arg317Gln located in the central domain of UGDH protein structure. (C) Cartoon representation of the dimeric structure of NADH and UDP-Glc-bound hUGDH in blue (Chain E) and gray (Chain F) (PDB ID: 2Q3E), with an R317Q mutation shown in pink. Highlighted are the helices α10–α13 (lemon and light pink colors for Chains E and F, respectively) forming the inter-dimer interface. Arg260 interacting with UDP-Glc is highlighted in red. (D) Cartoon representation of the mimeric structure of hUGDH bound to NADH and UDP-Glc (Chain E). Highlighted are the residues (Glu460, Thr461, Phe314, and Phe439) in pale green that interact with Arg317 in the wild-type protein and may likely become lost in an R317Q mutant. (E) Alignment of the sequences of H. sapiens UGDH (UniProt: O60701) with M. musculus (UniProt: O70475), R. norvegicus (UniProt: 070199), D. rerio (UniProt: A8WGP7), and O. cuniculus (UniProt: G1SP48). Arg317 (in pink) and its interacting residues Glu460, Thr461, Phe314, and Phe439 (in pale green) are highlighted. The alignment file was generated using UniProt Align (https://www.uniprot.org/align/), and final processing was performed in ESPript (http://espript.ibcp.fr).