Mutation Update forGNEGene Variants Associated with GNE Myopathy

Abstract

The GNE gene encodes the rate-limiting, bifunctional enzyme of sialic acid biosynthesis, UDP-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 7 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 as 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.

Identification of an Alu element‐mediated deletion in the promoter region of GNE in siblings with GNE myopathy

“…2013; Celeste et al. 2014). The other mutation is a novel 11.3‐kb deletion located in the 5′ UTR and promoter region of hGNE .…”

Atypical presentation of GNE myopathy with asymmetric hand weakness

“…This panethnic disorder has an estimated prevalence of ~4–21/1,000,000 worldwide [2], and of 1:1500 in the Iranian Jewish population [1]. The disease has been previously referred to as Hereditary Inclusion Body Myopathy (HIBM), Inclusion Body Myopathy 2 (IBM2; OMIM 600737), Distal Myopathy with Rimmed Vacuoles (DMRV) or Nonaka Myopathy (OMIM 605820) [3].…”

“…Muscle magnetic resonance imaging (MRI) of patients with GNE myopathy is characterized by T2-weighted short tau inversion recovery (STIR) hyperintensity of affected muscles in early stages, followed by fatty-fibrous replacement on T1-weighted imaging [11]. The diagnosis is confirmed by identification of biallelic GNE gene mutations [2]. The diagnosis of GNE myopathy can be challenging because of the disorder’s rarity [10], and can become more difficult in patients with an atypical presentation.…”

Aberrant O‐GlcNAcylation disrupts GNE enzyme activity in GNE myopathy

“…Previously, 122 of reported mutations so far, which could lead to a phenotype of GNE myopathy, are missense mutations. Approximately 23% of these mutations will be substituted in the protein sequence to threonine (T) or serine (S) [8]. Here, we examined the GNE-variant M743T (previously called M712T) [9].…”

“…A total of 154 mutations in the gene of GNE have been identified so far, likely leading to reduced GNE enzymatic activities [8]. Mutations in the GNE sequence are involved in the development of the neuromuscular disorder GNE myopathy (formerly hereditary inclusion body myopathy, HIBM), which accompany with a progressive amyotrophia during aging [9,10].…”