title: Genetics of GNE myopathy in the non-Jewish Persian population.
abstract: GNE myopathy is an autosomal recessive adult-onset disorder characterized by progressive muscle atrophy and weakness, initially involving the distal muscles, while often sparing the quadriceps. It is caused by variants in the GNE gene that encodes a key bifunctional enzyme in the sialic acid biosynthetic pathway. We investigated the clinical and molecular characteristics of 18 non-Jewish Persian patients from 11 unrelated GNE myopathy families. In addition, we reviewed the previously reported cases and suggest genotype-phenotype correlations for the identified variants. Comprehensive clinical and laboratory evaluations were carried out. Sequencing of the GNE gene was performed using genomic DNA from the patients. Screening of the identified variants was performed in all relevant family members. Molecular analyses identified three causative homozygous GNE variants in 11 families: c.2228T>C (p. M743T) in 7, c.830G>A (p.R277Q) in 2, and one novel variation (c.804G>A) in 2 families that results in a synonymous codon change (p.L268=) and likely creates a novel splice site affecting the protein function. This study confirms that c.2228T>C (p.M743T) is the most prevalent disease-causing variant in the non-Jewish Persian population, but other GNE variants can cause GNE myopathy in this population. The patients with all three different variants had similar ages of onset. The youngest patient was an 18-year-old girl in whom the c.830G>A (p.R277Q) variant was identified, whereas the oldest onset age (31 years) was seen in a male patient with c.804G>A (p.L268=). The results of this investigation expand our knowledge about the genotype-phenotype correlations in GNE myopathy and aid in clinical management and therapeutic interventions.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, USA.|Department of Medicine and the Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA, USA.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Alireza
authors.initials: A
authors.lastname: Haghighi
authors.affiliation: Department of Neurology, Iranian Center of Neurological Research, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran.
authors.forename: Shahriar
authors.initials: S
authors.lastname: Nafissi
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Abrar
authors.initials: A
authors.lastname: Qurashi
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Department of Neurology, Iranian Center of Neurological Research, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran.
authors.forename: Hosein
authors.initials: H
authors.lastname: Shamshiri
authors.affiliation: Department of Pathology, Pediatric Pathology Research Center, Mofid Children Hospital, Shahid Beheshti Medical University, Tehran, Iran.
authors.forename: Yalda
authors.initials: Y
authors.lastname: Nilipour
authors.affiliation: Toronto General Hospital, University of Toronto, Toronto, Canada.
authors.forename: Amirreza
authors.initials: A
authors.lastname: Haghighi
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Kornreich
mesh_terms: D000328:Adult; D049310:Distal Myopathies / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D007492:Iran; D007585:Jews / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: D009097:Multienzyme Complexes; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase