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Exome sequencing detection of two untranslated GFPT1 mutations in a family with limb-girdle myasthenia.

Publication ,  Journal Article
Maselli, RA; Arredondo, J; Nguyen, J; Lara, M; Ng, F; Ngo, M; Pham, JM; Yi, Q; Stajich, JM; McDonald, K; Hauser, MA; Wollmann, RL
Published in: Clin Genet
February 2014

The term 'limb-girdle myasthenia' (LGM) was first used to describe three siblings with proximal limb weakness without oculobulbar involvement, but with EMG decrement and responsiveness to anticholinesterase medication. We report here that exome sequencing in the proband of this family revealed several sequence variations in genes linked to proximal limb weakness. However, the only mutations that cosegregated with disease were an intronic IVS7-8A>G mutation and the previously reported 3'-UTR c.*22C>A mutation in GFPT1, a gene linked to LGM. A minigene assay showed that IVS7-8A>G activates an alternative splice acceptor that results in retention of the last seven nucleotides of intron 7 and a frameshift leading to a termination codon 13 nucleotides downstream from the new splice site. An anconeus muscle biopsy revealed mild reduction of the axon terminal size and postsynaptic fold simplification. The amplitudes of miniature endplate potentials and quantal release were also diminished. The DNA of the mildly affected father of the proband showed only the intronic mutation along with sequence variations in other genes potentially relevant to LGM. Thus, this study performed in the family originally described with LGM showed two GFPT1 untranslated mutations, which may cause disease by reducing GFPT1 expression and ultimately impairing protein glycosylation.

Duke Scholars

Published In

Clin Genet

DOI

EISSN

1399-0004

Publication Date

February 2014

Volume

85

Issue

2

Start / End Page

166 / 171

Location

Denmark

Related Subject Headings

  • Reverse Transcriptase Polymerase Chain Reaction
  • Pedigree
  • Neuromuscular Junction
  • Neostigmine
  • Myasthenic Syndromes, Congenital
  • Myasthenia Gravis
  • Molecular Sequence Data
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
 

Citation

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ICMJE
MLA
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Maselli, R. A., Arredondo, J., Nguyen, J., Lara, M., Ng, F., Ngo, M., … Wollmann, R. L. (2014). Exome sequencing detection of two untranslated GFPT1 mutations in a family with limb-girdle myasthenia. Clin Genet, 85(2), 166–171. https://doi.org/10.1111/cge.12118
Maselli, R. A., J. Arredondo, J. Nguyen, M. Lara, F. Ng, M. Ngo, J. M. Pham, et al. “Exome sequencing detection of two untranslated GFPT1 mutations in a family with limb-girdle myasthenia.Clin Genet 85, no. 2 (February 2014): 166–71. https://doi.org/10.1111/cge.12118.
Maselli RA, Arredondo J, Nguyen J, Lara M, Ng F, Ngo M, et al. Exome sequencing detection of two untranslated GFPT1 mutations in a family with limb-girdle myasthenia. Clin Genet. 2014 Feb;85(2):166–71.
Maselli, R. A., et al. “Exome sequencing detection of two untranslated GFPT1 mutations in a family with limb-girdle myasthenia.Clin Genet, vol. 85, no. 2, Feb. 2014, pp. 166–71. Pubmed, doi:10.1111/cge.12118.
Maselli RA, Arredondo J, Nguyen J, Lara M, Ng F, Ngo M, Pham JM, Yi Q, Stajich JM, McDonald K, Hauser MA, Wollmann RL. Exome sequencing detection of two untranslated GFPT1 mutations in a family with limb-girdle myasthenia. Clin Genet. 2014 Feb;85(2):166–171.
Journal cover image

Published In

Clin Genet

DOI

EISSN

1399-0004

Publication Date

February 2014

Volume

85

Issue

2

Start / End Page

166 / 171

Location

Denmark

Related Subject Headings

  • Reverse Transcriptase Polymerase Chain Reaction
  • Pedigree
  • Neuromuscular Junction
  • Neostigmine
  • Myasthenic Syndromes, Congenital
  • Myasthenia Gravis
  • Molecular Sequence Data
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)