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.
|Titolo:||ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases|
MAGRI, FRANCESCA MARIA BENEDETTA (Primo)
COLOMBO, IRENE (Secondo)
BRESOLIN, NEREO (Penultimo)
COMI, GIACOMO PIETRO (Corresponding)
|Parole Chiave:||aα-dystroglycan glycosylation; GDP-mannose pyrophosphorylase B; Isoprenoid synthase domain-containing gene; Limb Girdle Muscular Dystrophy; Neurology (clinical)|
|Settore Scientifico Disciplinare:||Settore MED/26 - Neurologia|
|Data di pubblicazione:||24-set-2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1186/s12883-015-0428-8|
|Appare nelle tipologie:||01 - Articolo su periodico|