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, 24 (2), 243-51

Genetics of GNE Myopathy in the non-Jewish Persian Population

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Genetics of GNE Myopathy in the non-Jewish Persian Population

Alireza Haghighi et al. Eur J Hum Genet.

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.

Figures

Figure 1
Figure 1
Geographical distribution of GNE variants in Iran. Numbers in the map represent the family numbers in Table 1. The black asterix shows the location of Sangsar.
Figure 2
Figure 2
Thighs (a) and legs (b) T1-weighted MR images (patient 7b). (a) Atrophy and fat replacement of posterior thigh muscles with relative sparing of quadriceps (white arrow) and sartorius muscles. (b) Fatty replacement in anterior and posterior leg muscles with relatively less involvement of the lateral head of gastrocnemius muscle (white arrow).
Figure 3
Figure 3
Pathological characteristics of GNE myopathy. (a) Red-rimmed cytoplasmic vacuoles showed by arrows (Gomori trichrome, high power, patient 9c muscle biopsy from right anterior tibialis). (b) Group atrophy (arrow) associated with prominent cytoplasmic vacuoles (arrowheads; H&E, high power, patient 9c muscle biopsy from right anterior tibialis). (c) Large group atrophy (arrow) resembling ‘spinal muscular atrophy' (H&E, medium power, patient 11b muscle biopsy from left biceps). (d) Dispersed or small group of angulated atrophic fibers (arrow) resembling ‘neurogenic atrophy' (H&E, high power, patient 8 muscle biopsy from left biceps). The full colour version of this figure is available at European Journal of Human Genetics online.

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