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

Abstract

BACKGROUND:

Limb Girdle Muscular Dystrophy (LGMD), caused by defective α-dystroglycan (α-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 α-DG immunohistochemistry (IHC) and mutation screening in patients with documented α-DG defect, or by direct DNA sequencing of both genes when muscle tissue was unavailable.

RESULTS:

We performed α-DG IHC in 27/39 undiagnosed probands: 24 subjects had normal α-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 α-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 α-DG defects is greater than previously realized.

• Authors: 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
• Journal: BMC neurology (BMC Neurol) Vol. 15 Pg. 172 (Sep 24 2015) ISSN: 1471-2377 [Electronic] England
• PMID: 26404900 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nucleotidyltransferases
• mannose 1-phosphate guanylyltransferase
• CRPPA protein, human

Topics

• Cohort Studies
• Humans
• Italy
• Muscular Dystrophies, Limb-Girdle (genetics)
• Mutation
• Nucleotidyltransferases (genetics)
• White People (genetics)