The human glucocerebrosidase gene and pseudogene: Structure and evolution

Horowitz, Mia; Wilder, Sylvia; Horowitz, Zeev; Reiner, Orly; Gelbart, Terri; Beutler, Ernest

doi:10.1016/0888-7543(89)90319-4

Cited by 387 publications

(305 citation statements)

References 28 publications

Supporting

Mentioning

293

Contrasting

Unclassified

Order By: Relevance

“…The high homology between GBA and its neighboring pseudogene ( GBAP1 ), which share 96% of sequence identity, not only explains several gene‐pseudogene rearrangements and gene‐conversion events12 but also complicates the analysis of the whole region 13. Our analysis disclosed 4 individuals presenting CNVs along the GBA‐GBAP1 region (see Figure 1B).…”

Section: Resultsmentioning

confidence: 93%

Detection of genomic rearrangements from targeted resequencing data in Parkinson's disease patients

et al. 2016

View full text Add to dashboard Cite

BackgroundThe analysis of coverage depth in next‐generation sequencing data allows the detection of gene dose alterations. We explore the frequency of such structural events in a Spanish cohort of sporadic PD cases.MethodsGene dose alterations were detected with the eXome‐Hidden Markov Model (XHMM) software from depth of coverage in resequencing data available for 38 Mendelian and other risk PD loci in 394 individuals (249 cases and 145 controls) and subsequently validated by quantitative PCR.ResultsWe identified 10 PD patients with exon dosage alterations in PARK2, GBA‐GBAP1, and DJ1. Additional functional variants, including 2 novel nonsense mutations (p.Arg1552Ter in LRRK2 and p.Trp90Ter in PINK1), were confirmed by Sanger sequencing. This combined approach disclosed the genetic cause of 12 PD cases.ConclusionsGene dose alterations related to PD can be correctly identified from targeting resequencing data. This approach substantially improves the detection rate of cases with causal genetic alterations. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

show abstract

Section: Resultsmentioning

confidence: 93%

Detection of genomic rearrangements from targeted resequencing data in Parkinson's disease patients

et al. 2016

View full text Add to dashboard Cite

show abstract

“…J03060.1) has been located 16 kb downstream from the active gene. 2 More than 300 mutations in the GBA gene have been reported to date, including all kind of defects such as single base changes, splicing alterations, insertions, partial and total deletions and gene-pseudogene rearrangements (www.hgmd.org). 3 GBA protein is synthesized on polyribosomes as a 55-kDa peptide, which is then translocated into the endoplasmic reticulum (ER), where it is modified by the addition of high mannose oligosaccharides, and transported to the trans-Golgi network, from where it is trafficked to the lysosomes.…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of 11 novel GBA alleles

et al. 2013

View full text Add to dashboard Cite

Gaucher disease is the most frequent lysosomal storage disorder due to the deficiency of the acid b-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.589-1G4A) and 9 (c.1389-1G4A), 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.

show abstract

“…There is a nonfunctional pseudo-GBA gene, found 16 kb downstream of the functional GBA gene, which shares 96% sequence similarity, but contains exonic and intronic deletions and nucleotide substitutions [4,5]. Presence of the pseudo-GBA gene has made it difficult to carry out GBA mutation analysis in GD patients [6].…”

Section: Introductionmentioning

confidence: 99%

“…Presence of the pseudo-GBA gene has made it difficult to carry out GBA mutation analysis in GD patients [6]. There are also a metaxin 1 pseudogene (pseudo-MTX1) located just downstream of the functional GBA gene, and the functional metaxin 1 gene (MTX1) located just downstream of the pseudo-GBA gene [4][5][6].…”

Section: Introductionmentioning

confidence: 99%