Mutation update for GNE gene variants associated with GNE myopathy

Abstract

The GNE gene encodes the rate-limiting, bifunctional enzyme of sialic acid biosynthesis, uridine diphosphate-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). Biallelic GNE mutations underlie GNE myopathy, an adult-onset progressive myopathy. GNE myopathy-associated GNE mutations are predominantly missense, resulting in reduced, but not absent, GNE enzyme activities. The exact pathomechanism of GNE myopathy remains unknown, but likely involves aberrant (muscle) sialylation. Here, we summarize 154 reported and novel GNE variants associated with GNE myopathy, including 122 missense, 11 nonsense, 14 insertion/deletions, and seven intronic variants. All variants were deposited in the online GNE variation database (http://www.dmd.nl/nmdb2/home.php?select_db=GNE). We report the predicted effects on protein function of all variants well as the predicted effects on epimerase and/or kinase enzymatic activities of selected variants. By analyzing exome sequence databases, we identified three frequently occurring, unreported GNE missense variants/polymorphisms, important for future sequence interpretations. Based on allele frequencies, we estimate the world-wide prevalence of GNE myopathy to be ∼4-21/1,000,000. This previously unrecognized high prevalence confirms suspicions that many patients may escape diagnosis. Awareness among physicians for GNE myopathy is essential for the identification of new patients, which is required for better understanding of the disorder's pathomechanism and for the success of ongoing treatment trials.

Keywords: DMRV; GNE; HIBM; adult onset muscular dystrophy; distal myopathy with rimmed vacuoles; hereditary inclusion body myopathy.

Figure 1. Schematic illustration (not to scale) of the GNE gene and protein and location of sequence variants associated with GNE myopathy

A: Exon (boxes)-intron (lines) structure of the human GNE gene. White boxes = untranslated region; light gray boxes = encoding UDP-GlcNAc 2-epimerase enzymatic activity; dark gray boxes = encoding ManNAc kinase enzymatic activity; vertical striped boxes = protein domains indicated in (B). Locations and characteristics of all reported human GNE variants associated with GNE myopathy (as of January 2014) are indicated. Variant nomenclature is according to the longest mRNA splice variant (Variant 1; NM_001128227.2) and its translated protein isoform hGNE2 (NP_001121699.1). Exon numbering is according to the GNE genomic DNA sequence (NC_000009.12). Truncating nonsense and indel variants are printed in bold, intronic variants in gray highlight. The large deletion variant del ex 2–10 (>35.7kb) is not displayed. The pie chart visualizes the overall distribution of variants. B: Protein structure of the hGNE2 isoform. Functional domains are indicated as vertical striped regions: UF, unknown function; NES, putative nuclear export signal (NES), AR, experimental allosteric region. Amino acid numbers of hGNE2 and hGNE1 are indicated below the structure. Note that amino acids 1-31 are only present in hGNE2. All other amino acids and protein domains are similar in hGNE1 and hGNE2.