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

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Abstract

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
Volume15
Issue number1
DOIs
Publication statusPublished - Sep 24 2015

Fingerprint

Dystroglycans
Limb-Girdle Muscular Dystrophies
Terpenes
Mutation
Genes
Immunohistochemistry
Genetic Heterogeneity
DNA Sequence Analysis
Glycosylation
Hypertrophy
Population
Walking
mannose 1-phosphate guanylyltransferase
Exons
Muscles

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

@article{70724d0ecef44de0b51dd0d5ad707c67,
title = "ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases",
abstract = "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.",
keywords = "aα-dystroglycan glycosylation, GDP-mannose pyrophosphorylase B, Isoprenoid synthase domain-containing gene, Limb Girdle Muscular Dystrophy",
author = "Francesca Magri and Irene Colombo and {Del Bo}, Roberto and Stefano Previtali and Roberta Brusa and Patrizia Ciscato and Marina Scarlato and Dario Ronchi and D'Angelo, {Maria Grazia} and Stefania Corti and Maurizio Moggio and Nereo Bresolin and Comi, {Giacomo Pietro}",
year = "2015",
month = "9",
day = "24",
doi = "10.1186/s12883-015-0428-8",
language = "English",
volume = "15",
journal = "BMC Neurology",
issn = "1471-2377",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases

AU - Magri, Francesca

AU - Colombo, Irene

AU - Del Bo, Roberto

AU - Previtali, Stefano

AU - Brusa, Roberta

AU - Ciscato, Patrizia

AU - Scarlato, Marina

AU - Ronchi, Dario

AU - D'Angelo, Maria Grazia

AU - Corti, Stefania

AU - Moggio, Maurizio

AU - Bresolin, Nereo

AU - Comi, Giacomo Pietro

PY - 2015/9/24

Y1 - 2015/9/24

N2 - 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.

AB - 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.

KW - aα-dystroglycan glycosylation

KW - GDP-mannose pyrophosphorylase B

KW - Isoprenoid synthase domain-containing gene

KW - Limb Girdle Muscular Dystrophy

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U2 - 10.1186/s12883-015-0428-8

DO - 10.1186/s12883-015-0428-8

M3 - Article

AN - SCOPUS:84942368865

VL - 15

JO - BMC Neurology

JF - BMC Neurology

SN - 1471-2377

IS - 1

M1 - 172

ER -