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.

ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases / F. Magri, I. Colombo, R. Del Bo, S. Previtali, R. Brusa, P. Ciscato, M. Scarlato, D. Ronchi, M.G. D'Angelo, S. Corti, M. Moggio, N. Bresolin, G.P. Comi. - In: BMC NEUROLOGY. - ISSN 1471-2377. - 15:1(2015 Sep 24), pp. 172.1-172.8. [10.1186/s12883-015-0428-8]

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

F. Magri
Primo
;
I. Colombo
Secondo
;
R. Del Bo;R. Brusa;M. Scarlato;D. Ronchi;M.G. D'Angelo;S. Corti;N. Bresolin
Penultimo
;
G.P. Comi
2015-09-24

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.
aα-dystroglycan glycosylation; GDP-mannose pyrophosphorylase B; Isoprenoid synthase domain-containing gene; Limb Girdle Muscular Dystrophy; Neurology (clinical)
Settore MED/26 - Neurologia
Article (author)
File in questo prodotto:
File Dimensione Formato  
art%3A10.1186%2Fs12883-015-0428-8.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 1.59 MB
Formato Adobe PDF
1.59 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/342616
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 7
  • ???jsp.display-item.citation.isi??? 5
social impact