Identification of an Alu element-mediated deletion in the promoter region of GNE in siblings with GNE myopathy

Jennifer Garland, Joshi Stephen, Bradley Class, Angela Gruber, Carla Ciccone, Aaron Poliak, Christina P. Hayes, Vandana Singhal, Christina Slota, John Perreault, Ralitza M Gavrilova, Joseph A. Shrader, Prashant Chittiboina, Galen Joe, John Heiss, William A. Gahl, Marjan Huizing, Nuria Carrillo, May Christine V. Malicdan

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: GNE myopathy is a rare genetic disease characterized by progressive muscle atrophy and weakness. It is caused by biallelic mutations in the GNE gene that encodes for the bifunctional enzyme, uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase. Typical characteristics of GNE myopathy include progressive myopathy, first involving anterior tibialis muscle and sparing the quadriceps, and rimmed vacuoles on muscle biopsy. Identifying biallelic mutations by sequencing of the GNE gene confirms the diagnosis of GNE myopathy. In a subset of patients, diagnostic confirmation is challenged by the identification of mutations in only one allele, suggesting mutations in deep intronic regions or regulatory regions. Methods: We performed targeted sequencing and copy number variant (CNV) analysis of GNE in two siblings who clinically presented with GNE myopathy. Further molecular and biochemical studies were done to characterize the effect of a previously uncharacterized GNE mutation. Results: We report two siblings of Indian descent with characteristic features of GNE myopathy, including progressive skeletal muscle weakness initially involving the anterior tibialis, and rimmed vacuoles on muscle biopsy, in which a heterozygous mutation, p.Val727Met, was identified in both affected siblings, but no other deleterious variants in either coding region or exon–intron boundaries of the gene. Subsequent insertion/deletion analysis identified a novel 11.3-kb deletion (Chr9 [GRCh37]: g.36257583_36268910del) encompassing the GNE promoter region, with breakpoints residing in Alu repeats. Gene expression analysis revealed reduced GNE mRNA and protein levels, confirming decreased expression of the deleted allele harboring the deletion. Conclusions: We have identified GNE as one of the genes susceptible to Alu-mediated recombination. Our findings suggest that the deletion may encompass the promoter or another region necessary for GNE expression. In patients with typical manifestations of GNE myopathy and a single GNE variant identified, copy number variant (CNV) analysis may be useful in arriving at the diagnosis.

Original languageEnglish (US)
Pages (from-to)410-417
Number of pages8
JournalMolecular Genetics and Genomic Medicine
Volume5
Issue number4
DOIs
StatePublished - Jan 1 2017

Fingerprint

Alu Elements
Muscular Diseases
Genetic Promoter Regions
Siblings
Mutation
N-acylmannosamine kinase
Muscle Weakness
Vacuoles
Genes
Alleles
Uridine Diphosphate N-Acetylglucosamine
Biopsy
Muscles
Inborn Genetic Diseases
Muscular Atrophy
Nucleic Acid Regulatory Sequences
Quadriceps Muscle
Rare Diseases
Genetic Recombination
Skeletal Muscle

Keywords

  • Alu-SINE repeat
  • array-CGH
  • copy number variant
  • genomic rearrangement
  • GNE isoforms
  • GNE myopathy
  • precision medicine
  • sialic acid

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Garland, J., Stephen, J., Class, B., Gruber, A., Ciccone, C., Poliak, A., ... Malicdan, M. C. V. (2017). Identification of an Alu element-mediated deletion in the promoter region of GNE in siblings with GNE myopathy. Molecular Genetics and Genomic Medicine, 5(4), 410-417. https://doi.org/10.1002/mgg3.300

Identification of an Alu element-mediated deletion in the promoter region of GNE in siblings with GNE myopathy. / Garland, Jennifer; Stephen, Joshi; Class, Bradley; Gruber, Angela; Ciccone, Carla; Poliak, Aaron; Hayes, Christina P.; Singhal, Vandana; Slota, Christina; Perreault, John; Gavrilova, Ralitza M; Shrader, Joseph A.; Chittiboina, Prashant; Joe, Galen; Heiss, John; Gahl, William A.; Huizing, Marjan; Carrillo, Nuria; Malicdan, May Christine V.

In: Molecular Genetics and Genomic Medicine, Vol. 5, No. 4, 01.01.2017, p. 410-417.

Research output: Contribution to journalArticle

Garland, J, Stephen, J, Class, B, Gruber, A, Ciccone, C, Poliak, A, Hayes, CP, Singhal, V, Slota, C, Perreault, J, Gavrilova, RM, Shrader, JA, Chittiboina, P, Joe, G, Heiss, J, Gahl, WA, Huizing, M, Carrillo, N & Malicdan, MCV 2017, 'Identification of an Alu element-mediated deletion in the promoter region of GNE in siblings with GNE myopathy', Molecular Genetics and Genomic Medicine, vol. 5, no. 4, pp. 410-417. https://doi.org/10.1002/mgg3.300
Garland, Jennifer ; Stephen, Joshi ; Class, Bradley ; Gruber, Angela ; Ciccone, Carla ; Poliak, Aaron ; Hayes, Christina P. ; Singhal, Vandana ; Slota, Christina ; Perreault, John ; Gavrilova, Ralitza M ; Shrader, Joseph A. ; Chittiboina, Prashant ; Joe, Galen ; Heiss, John ; Gahl, William A. ; Huizing, Marjan ; Carrillo, Nuria ; Malicdan, May Christine V. / Identification of an Alu element-mediated deletion in the promoter region of GNE in siblings with GNE myopathy. In: Molecular Genetics and Genomic Medicine. 2017 ; Vol. 5, No. 4. pp. 410-417.
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abstract = "Background: GNE myopathy is a rare genetic disease characterized by progressive muscle atrophy and weakness. It is caused by biallelic mutations in the GNE gene that encodes for the bifunctional enzyme, uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase. Typical characteristics of GNE myopathy include progressive myopathy, first involving anterior tibialis muscle and sparing the quadriceps, and rimmed vacuoles on muscle biopsy. Identifying biallelic mutations by sequencing of the GNE gene confirms the diagnosis of GNE myopathy. In a subset of patients, diagnostic confirmation is challenged by the identification of mutations in only one allele, suggesting mutations in deep intronic regions or regulatory regions. Methods: We performed targeted sequencing and copy number variant (CNV) analysis of GNE in two siblings who clinically presented with GNE myopathy. Further molecular and biochemical studies were done to characterize the effect of a previously uncharacterized GNE mutation. Results: We report two siblings of Indian descent with characteristic features of GNE myopathy, including progressive skeletal muscle weakness initially involving the anterior tibialis, and rimmed vacuoles on muscle biopsy, in which a heterozygous mutation, p.Val727Met, was identified in both affected siblings, but no other deleterious variants in either coding region or exon–intron boundaries of the gene. Subsequent insertion/deletion analysis identified a novel 11.3-kb deletion (Chr9 [GRCh37]: g.36257583_36268910del) encompassing the GNE promoter region, with breakpoints residing in Alu repeats. Gene expression analysis revealed reduced GNE mRNA and protein levels, confirming decreased expression of the deleted allele harboring the deletion. Conclusions: We have identified GNE as one of the genes susceptible to Alu-mediated recombination. Our findings suggest that the deletion may encompass the promoter or another region necessary for GNE expression. In patients with typical manifestations of GNE myopathy and a single GNE variant identified, copy number variant (CNV) analysis may be useful in arriving at the diagnosis.",
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T1 - Identification of an Alu element-mediated deletion in the promoter region of GNE in siblings with GNE myopathy

AU - Garland, Jennifer

AU - Stephen, Joshi

AU - Class, Bradley

AU - Gruber, Angela

AU - Ciccone, Carla

AU - Poliak, Aaron

AU - Hayes, Christina P.

AU - Singhal, Vandana

AU - Slota, Christina

AU - Perreault, John

AU - Gavrilova, Ralitza M

AU - Shrader, Joseph A.

AU - Chittiboina, Prashant

AU - Joe, Galen

AU - Heiss, John

AU - Gahl, William A.

AU - Huizing, Marjan

AU - Carrillo, Nuria

AU - Malicdan, May Christine V.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background: GNE myopathy is a rare genetic disease characterized by progressive muscle atrophy and weakness. It is caused by biallelic mutations in the GNE gene that encodes for the bifunctional enzyme, uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase. Typical characteristics of GNE myopathy include progressive myopathy, first involving anterior tibialis muscle and sparing the quadriceps, and rimmed vacuoles on muscle biopsy. Identifying biallelic mutations by sequencing of the GNE gene confirms the diagnosis of GNE myopathy. In a subset of patients, diagnostic confirmation is challenged by the identification of mutations in only one allele, suggesting mutations in deep intronic regions or regulatory regions. Methods: We performed targeted sequencing and copy number variant (CNV) analysis of GNE in two siblings who clinically presented with GNE myopathy. Further molecular and biochemical studies were done to characterize the effect of a previously uncharacterized GNE mutation. Results: We report two siblings of Indian descent with characteristic features of GNE myopathy, including progressive skeletal muscle weakness initially involving the anterior tibialis, and rimmed vacuoles on muscle biopsy, in which a heterozygous mutation, p.Val727Met, was identified in both affected siblings, but no other deleterious variants in either coding region or exon–intron boundaries of the gene. Subsequent insertion/deletion analysis identified a novel 11.3-kb deletion (Chr9 [GRCh37]: g.36257583_36268910del) encompassing the GNE promoter region, with breakpoints residing in Alu repeats. Gene expression analysis revealed reduced GNE mRNA and protein levels, confirming decreased expression of the deleted allele harboring the deletion. Conclusions: We have identified GNE as one of the genes susceptible to Alu-mediated recombination. Our findings suggest that the deletion may encompass the promoter or another region necessary for GNE expression. In patients with typical manifestations of GNE myopathy and a single GNE variant identified, copy number variant (CNV) analysis may be useful in arriving at the diagnosis.

AB - Background: GNE myopathy is a rare genetic disease characterized by progressive muscle atrophy and weakness. It is caused by biallelic mutations in the GNE gene that encodes for the bifunctional enzyme, uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase. Typical characteristics of GNE myopathy include progressive myopathy, first involving anterior tibialis muscle and sparing the quadriceps, and rimmed vacuoles on muscle biopsy. Identifying biallelic mutations by sequencing of the GNE gene confirms the diagnosis of GNE myopathy. In a subset of patients, diagnostic confirmation is challenged by the identification of mutations in only one allele, suggesting mutations in deep intronic regions or regulatory regions. Methods: We performed targeted sequencing and copy number variant (CNV) analysis of GNE in two siblings who clinically presented with GNE myopathy. Further molecular and biochemical studies were done to characterize the effect of a previously uncharacterized GNE mutation. Results: We report two siblings of Indian descent with characteristic features of GNE myopathy, including progressive skeletal muscle weakness initially involving the anterior tibialis, and rimmed vacuoles on muscle biopsy, in which a heterozygous mutation, p.Val727Met, was identified in both affected siblings, but no other deleterious variants in either coding region or exon–intron boundaries of the gene. Subsequent insertion/deletion analysis identified a novel 11.3-kb deletion (Chr9 [GRCh37]: g.36257583_36268910del) encompassing the GNE promoter region, with breakpoints residing in Alu repeats. Gene expression analysis revealed reduced GNE mRNA and protein levels, confirming decreased expression of the deleted allele harboring the deletion. Conclusions: We have identified GNE as one of the genes susceptible to Alu-mediated recombination. Our findings suggest that the deletion may encompass the promoter or another region necessary for GNE expression. In patients with typical manifestations of GNE myopathy and a single GNE variant identified, copy number variant (CNV) analysis may be useful in arriving at the diagnosis.

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