Novel GNE Mutations in Autosomal Recessive Hereditary Inclusion Body Myopathy Patients

Abstract

Hereditary Inclusion Body Myopathy (HIBM, IBM2, MIM:600737) is an autosomal recessive adult onset progressive muscle wasting disorder. It is associated with the degeneration of distal and proximal muscles, while often sparing the quadriceps. The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE/MNK), encoded by the GNE gene, catalyzes the first two committed, rate-limiting steps in the biosynthesis of N-acetylneunaminic acid (sialic acid). Affected individuals have been identified with mutations in the GNE gene. In the present study, the GNE coding region of 136 symptomatic patients were sequenced. A total of 41 patients were found to have GNE mutations. Eight novel mutations were discovered among seven patients. Of the eight novel mutations, seven were missense (p.I150V, p.Y186C, p.M265T, p.V315T, p.N317D, p.G669R, and p.S699L) and one was nonsense (p.W495X), all of which span the epimerase, kinase, and allosteric domains of GNE. In one patient, one novel mutation was found in the allosteric region and kinase domain of the GNE gene. Mutations in the allosteric region lead to a different disease, sialuria; however, this particular mutation has not been described in patients with sialuria. The pathological significance of this variation with GNE function remains unknown and further studies are needed to identify its connection with HIBM. These findings further expand the clinical and genetic spectrum of HIBM.

Identification of a GNE homozygous mutation in a Han‐Chinese family with GNE myopathy

“…The patients here presented well‐known typical clinical features of GNE myopathy, including progressive distal muscular atrophy and weakness. These are consistent with the reports of prior studies . It is distinguishable from atypical patients who had at least one allele mutation in the non‐kinase domain .…”

“…These are consistent with the reports of prior studies . It is distinguishable from atypical patients who had at least one allele mutation in the non‐kinase domain . The presence of different genetic backgrounds, epigenetic factors and/or modifying environmental events may contribute significantly to the clinical manifestations .…”

“…To date, more than 201 GNE mutations across the entire coding region have been reported. They span the epimerase and kinase domains, and allosteric region . Middle Eastern mutation c.2228T>C (p.M743T) appears predominantly in those of Middle Eastern population, while c.1807G>C (p.V603L) and c.620A>T (p.D207V) are most common in Japanese patients …”

“…It has a higher prevalence in Middle Eastern Jews and Japanese. GNE myopathy is caused by the mutations in the UDP‐N‐acetylglucosamine 2‐epimerase/N‐acetylmannosamine kinase gene ( GNE ), which encodes the bifunctional enzyme catalysing the first two rate‐limiting steps in sialic acid biosynthesis …”

“…GNE myopathy is caused by the mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene (GNE), which encodes the bifunctional enzyme catalysing the first two rate-limiting steps in sialic acid biosynthesis. 5 In this study, targeted exome capture and high-throughput sequencing of 411 known genes involved in neuromuscular disorders were performed to identify genetic causes of an autosomal recessive GNE myopathy in a three-generation Han-Chinese pedigree. 6 A homozygous missense mutation, c.1627G>A (p.V543M), in the GNE gene was found to co-segregate with the GNE myopathy present in this family.…”