An investigation of the properties and possible clinical significance of the lysosomal α‐glucosidase GAA* 2 allele

Dm, Swallow; Kroos, Marian A.; Ploeg, Ans T. van der; Griffiths, Beatrice; Islam, I; Marenah, C B; Reuser, Arnold

doi:10.1111/j.1469-1809.1989.tb01782.x

Cited by 17 publications

(18 citation statements)

References 14 publications

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“…These variants have previously been shown to lower GAA enzymatic activity to some extent, however, they cannot cause Pompe disease (M.A. Kroos et al, ; Shigeto et al, ; Swallow et al, ; van Diggelen et al, ).…”

Section: Resultsmentioning

confidence: 99%

Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity

et al. 2019

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Pompe disease is an autosomal recessive lysosomal storage disorder caused by disease‐associated variants in the acid alpha‐glucosidase (GAA) gene. The current Pompe mutation database provides a severity rating of GAA variants based on in silico predictions and expression studies. Here, we extended the database with clinical information of reported phenotypes. We added additional in silico predictions for effects on splicing and protein function and for cross reactive immunologic material (CRIM) status, minor allele frequencies, and molecular analyses. We analyzed 867 patients and 562 GAA variants. Based on their combination with a GAA null allele (i.e., complete deficiency of GAA enzyme activity), 49% of the 422 disease‐associated variants could be linked to classic infantile, childhood, or adult phenotypes. Predictions and immunoblot analyses identified 131 CRIM negative and 216 CRIM positive variants. While disease‐associated missense variants were found throughout the GAA protein, they were enriched up to seven‐fold in the catalytic site. Fifteen percent of disease‐associated missense variants were predicted to affect splicing. This should be confirmed using splicing assays. Inclusion of clinical severity rating in the Pompe mutation database provides an invaluable tool for diagnosis, prognosis of disease progression, treatment regimens, and the future development of personalized medicine for Pompe disease.

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Section: Resultsmentioning

confidence: 99%

Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity

et al. 2019

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“…The GAA2 allele is characterized by the sequence variation c.271G> A [46] and occurs in Caucasian populations with a carrier frequency of 1 in 16 [47,48]. The resulting amino acid substitution p.Asp91Asn has the peculiar feature that it reduces the affinity of acid a-glucosidase for glycogen but not for MUaGlc.…”

Section: Diagnostic Specimens: Leukocytesmentioning

confidence: 99%

Enzymatic and molecular strategies to diagnose Pompe disease

Reuser

Verheijen

Kroos

et al. 2009

Expert Opinion on Medical Diagnostics

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Enzyme replacement therapy for Pompe disease, a neuromuscular disorder characterized by lysosomal glycogen storage due to acid α-glucosidase deficiency, has entered the clinic. There is more than ever a need for early and reliable diagnosis. The objective of this review is to present a critical review of the recent literature on laboratory procedures to diagnose Pompe disease by enzymatic assay and DNA analysis. The methods we used were Compilation and expert interpretation of recent and relevant publications. The introduction of new and the updating of existing laboratory procedures have facilitated the diagnosis of Pompe disease (glycogen storage disease type II; acid maltase deficiency; OMIM 232300). With regard to enzymatic analysis, the application of acarbose as inhibitor of maltase-glucoamylase has enabled the use of mixed leukocyte preparations as diagnostic material. The use of glycogen as a natural substrate in the reaction mixture adds to the selectivity of this procedure. Newborn screening is envisaged and facilitated by the introduction of high-throughput procedures. DNA analysis has become an integral part of the diagnostic procedure for confirmation and completion, for carrier detection, and for genetic counseling.

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“…Multiple forms of human GAA enzyme have also been observed in different populations. The GAA2 form characterized by an NP_000143.2:p.Asp91Asn variant, has lower enzyme affinity for glycogen (Beratis, LaBadie, & Hirschhorn, ; Swallow et al, ). Another form of the GAA enzyme termed GAA4, characterized by the NP_000143.2:p.Glu689Lys variant is especially prevalent in Asian populations (allele frequency of 0.29).…”

Section: Discussionmentioning

confidence: 99%

Gene‐specific features enhance interpretation of mutational impact on acid α‐glucosidase enzyme activity

Adhikari

2019

Human Mutation

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We present a computational model for predicting mutational impact on enzymatic activity of human acid α‐glucosidase (GAA), an enzyme associated with Pompe disease. Using a model that combines features specific to GAA with other general evolutionary and physiochemical features, we made blind predictions of enzymatic activity relative to wildtype human GAA for >300 GAA mutants, as part of the Critical Assessment of Genome Interpretation 5 GAA challenge. We found that gene‐specific features can improve the performance of existing impact prediction tools that mostly rely on general features for pathogenicity prediction. Majority of the poorly predicted mutants that lower wildtype GAA enzyme activity occurred on the surface of the GAA protein. We also found that gene‐specific features were uncorrelated with existing methods and provided orthogonal information for interpreting the origin of pathogenicity, particular in variants that are poorly predicted by existing general methods. Specific variants in GAA, when investigated in the context of its protein structure, suggested gene‐specific information like the disruption of local backbone torsional geometry and disruption of particular sidechain‐sidechain hydrogen bonds as some potential sources for pathogenicity.

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An investigation of the properties and possible clinical significance of the lysosomal α‐glucosidase GAA* 2 allele

Cited by 17 publications

References 14 publications

Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity

Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity

Enzymatic and molecular strategies to diagnose Pompe disease

Gene‐specific features enhance interpretation of mutational impact on acid α‐glucosidase enzyme activity

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