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Eur J Hum Genet. 2014 Apr;22(4):511-6. doi: 10.1038/ejhg.2013.182. Epub 2013 Sep 11.

Functional analysis of 11 novel GBA alleles.

Author information

  • 1Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
  • 2U.O.S.D. Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, Istituto G. Gaslini, Genova, Italy.
  • 3Patologia Molecolare Integrata - A.O.U. IRCSS San Martino - IST, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
  • 4Rare Metabolic Diseases Unit, Pediatric Clinic, San Gerardo Hospital, Monza, Italy.


Gaucher disease is the most frequent lysosomal storage disorder due to the deficiency of the acid β-glucosidase, encoded by the GBA gene. In this study, we report the structural and functional characterization of 11 novel GBA alleles. Seven single missense alleles, P159S, N188I, E235K, P245T, W312S, S366R and W381C, and two alleles carrying in cis mutations, (N188S; G265R) and (E326K; D380N), were studied for enzyme activity in transiently transfected cells. All mutants were inactive except the P159S, which retained 15% of wild-type activity. To further characterize the alleles carrying two in cis mutations, we expressed constructs bearing singly each mutation. The presence of G265R or D380N mutations completely abolished enzyme activity, while N188S and E326K mutants retained 25 and 54% of wild-type activity, respectively. Two mutations, affecting the acceptor splice site of introns 5 (c.589-1G>A) and 9 (c.1389-1G>A), led to the synthesis of aberrant mRNA. Unpredictably, family studies showed that two alleles resulted from germline or 'de novo' mutations. These results strengthen the importance of performing a complete and accurate molecular analysis of the GBA gene in order to avoid misleading conclusions and provide a comprehensive functional analysis of new GBA mutations.

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[Available on 2015/4/1]
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