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BMC Neurology
Published in: BMC Neurology 1/2015

Open Access 01-12-2015 | Research article

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

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

Published in: BMC Neurology | Issue 1/2015

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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.
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Metadata
Title
ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases
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
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2015
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-015-0428-8

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