Novel missense mutation p.A310P in the GNE gene in autosomal-recessive hereditary inclusion-body myopathy/distal myopathy with rimmed vacuoles in an Italian family

Abstract

Autosomal-recessive hereditary inclusion-body myopathy with relative quadriceps sparing is associated with mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. Two Italian sisters affected with autosomal-recessive hIBM were shown to be compound heterozygous for a novel GNE mutation: a p.A310P amino acid change along with a p.R246W mutation on the second allele both in the epimerase domain. This is the first mutation event observed in a human GNE allele inducing a proline. Muscle biopsy showed abundant rimmed and non-rimmed vacuoles. Severe disease progression was noted in the elder sister. The Italian family further expands the wide phenotypic and genotypic spectrum of hIBM.

Introduction

The adult onset hereditary inclusion-body myopathy (hIBM, OMIM #600737) is characterized by muscle weakness and atrophy of lower limb muscles, which progresses proximally and relatively spares the quadriceps. The disorder was originally described in Iranian Jews [1] whereas the distal myopathy type Nonaka was characterized in Japan (distal myopathy with rimmed vacuoles, DMRV, OMIM #605820). Both disorders are autosomal-recessive and caused by mutations in the UDP-N-acetyl-glucosamine 2-epimerase/N–acetylmannosamine kinase (GNE) gene on chromosome 9p13.3 [2]. In the present case history we describe a novel compound heterozygous mutation in two Italian sisters.