title: 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.
authors.affiliation: Therapeutics for Rare and Neglected Diseases, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland.
authors.forename: Frank V
authors.initials: FV
authors.lastname: Celeste
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.forename: Carla
authors.initials: C
authors.lastname: Ciccone
authors.forename: John Karl
authors.initials: JK
authors.lastname: de Dios
authors.forename: May Christine V
authors.initials: MC
authors.lastname: Malicdan
authors.forename: Petcharat
authors.initials: P
authors.lastname: Leoyklang
authors.forename: John C
authors.initials: JC
authors.lastname: McKew
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Nuria
authors.initials: N
authors.lastname: Carrillo-Carrasco
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
mesh_terms: D000483:Alleles; D044466:Asian People; D030541:Databases, Genetic; D049310:Distal Myopathies / Q000208:ethnology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D059472:Exome; D005091:Exons; D015870:Gene Expression; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D006801:Humans; D007438:Introns; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D012794:Sialic Acids / Q000378:metabolism; D044465:White People
chemical_list: D009097:Multienzyme Complexes; D012794:Sialic Acids; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase
keywords: DMRV; GNE; HIBM; adult onset muscular dystrophy; distal myopathy with rimmed vacuoles; hereditary inclusion body myopathy