ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases

Francesca Magri, Irene Colombo, Roberto Del Bo, Stefano Previtali, Roberta Brusa, Patrizia Ciscato, Marina Scarlato, Dario Ronchi, Maria Grazia D'Angelo, Stefania Corti, Maurizio Moggio, Nereo Bresolin, Giacomo Pietro Comi

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Background: Limb Girdle Muscular Dystrophy (LGMD), caused by defective aα-dystroglycan (aα-DG) glycosylation, was recently associated with mutations in Isoprenoid synthase domain-containing (ISPD) and GDP-mannose pyrophosphorylase B (GMPPB) genes. The frequency of ISPD and GMPPB gene mutations in the LGMD population is unknown. Methods: We investigated the contributions of ISPD and GMPPB genes in a cohort of 174 Italian patients with LGMD, including 140 independent probands. Forty-one patients (39 probands) from this cohort had not been genetically diagnosed. The contributions of ISPD and GMPPB were estimated by sequential aα-DG immunohistochemistry (IHC) and mutation screening in patients with documented aα-DG defect, or by direct DNA sequencing of both genes when muscle tissue was unavailable. Results: We performed aα-DG IHC in 27/39 undiagnosed probands: 24 subjects had normal aα-DG expression, two had a partial deficiency, and one exhibited a complete absence of signal. Direct sequencing of ISPD and GMPPB revealed two heterozygous ISPD mutations in the individual who lacked aα-DG IHC signal: c.836-5 T > G (which led to the deletion of exon 6 and the production of an out-of-frame transcript) and c.676 T > C (p.Tyr226His). This patient presented with sural hypertrophy and tip-toed walking at 5 years, developed moderate proximal weakness, and was fully ambulant at 42 years. The remaining 12/39 probands did not exhibit pathogenic sequence variation in either gene. Conclusion:ISPD mutations are a rare cause of LGMD in the Italian population, accounting for less than 1 % of the entire cohort studied (FKRP mutations represent 10 %), while GMPPB mutations are notably absent in this patient sample. These data suggest that the genetic heterogeneity of LGMD with and without aα-DG defects is greater than previously realized.

Original languageEnglish
Article number172
JournalBMC Neurology
Issue number1
Publication statusPublished - Sept 24 2015


  • aα-dystroglycan glycosylation
  • GDP-mannose pyrophosphorylase B
  • Isoprenoid synthase domain-containing gene
  • Limb Girdle Muscular Dystrophy

ASJC Scopus subject areas

  • Clinical Neurology


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