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Intron retention is among six unreported AGL mutations identified in Malaysian GSD III patients

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Abstract

Background

Glycogen storage disease type III is an autosomal recessive disorder that is caused by deficiencies of the glycogen debranching enzyme. Mutations within the AGL gene have been found to be heterogeneous, with some common mutations being reported in certain populations. The mutation spectrum of AGL gene in the multi-ethnic Malaysian population is still unknown.

Objective

The present study seeks to determine the mutation spectrum of the AGL gene in Malaysian population.

Methods

A total of eleven patients (eight Malay, two Chinese and one Bajau) were investigated. Genomic DNA was extracted and subsequently the AGL gene was amplified using specific primers and sequenced. Mutations found were screened in 150 healthy control samples either by restriction enzyme digestion assay or TaqMan® SNP Genotyping assay.

Results

We identified six unreported mutations (c.1423+1G>T, c.2914_2915delAA, c.3814_3815delAG, c.4333T>G, c.4490G>A, c.4531_4534delTGTC) along with three previously reported mutations (c.99C>T, c.1783C>T, c.2681+1G>A). One of the six unreported mutation causes abnormal splicing and results in retention of intron 12 of the mature transcript, while another is a termination read-through. One of the reported mutation c.2681+1G>A was recurrently found in the Malay patients (n = 7 alleles; 31.8%).

Conclusion

The mutation spectrum of the AGL gene in Malaysian patients has shown considerable heterogeneity, and all unreported mutations were absent in all 150 healthy control samples tested.

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Acknowledgements

We thank University Malaya Medical Centre and Kuala Lumpur Hospital for providing blood samples or DNA samples of GSD III patients; Dr Heng Hock Sin for providing clinical data of patient 11; Assoc. Prof. Dr. Ng Ching Ching and Dr. Azlina Ahmad Annuar for providing DNA samples for population study; Centre for Research in Biotechnology for Agriculture (CEBAR), UM for contributing the sequencing platform. Lastly, we thank Ministry of Science, Technology and Innovation of Malaysia for the eScience fund (SF012-2012) and University of Malaya for the UM Biotechnology and Bioproduct Research Cluster fund (RG071-12BIO).

Funding

This study was funded by eScience fund (SF012-2012) and UM Biotechnology and Bioproduct Research Cluster fund (RG071-12BIO).

Author information

Authors and Affiliations

  1. Genetics and Molecular Biology Unit, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Ili Syazwana Abdullah, Ser-Huy Teh & Zulqarnain Mohamed

  2. Centre for Research in Biotechnology for Agriculture, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Fiqri Dizar Khaidizar

  3. Genetics Department, Kuala Lumpur Hospital, 50586, Kuala Lumpur, Malaysia

    Lock-Hock Ngu & Wee-Teik Keng

  4. Division of Inherited Metabolic Disorders, Department of Paediatrics, University Malaya Medical Centre and Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Sufin Yap

  5. Department of Inherited Metabolic Diseases, Sheffield Children’s Hospital, NHS Foundation Trust, Western Bank, S10 2TH, Sheffield, UK

    Sufin Yap

  6. Institute of Advanced Studies, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Zulqarnain Mohamed

Authors
  1. Ili Syazwana Abdullah
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  2. Ser-Huy Teh
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Corresponding author

Correspondence to Zulqarnain Mohamed.

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Conflict of interest

Ser-Huy Teh, Fiqri Dizar Khaidizar, Lock-Hock Ngu, Wee-Teik Keng, Sufin Yap, Zulqarnain Mohamed, and author declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This project was approved by the Medical Ethics Committee University Malaya Medical Centre reference number: UMMC MEC 2012/908.27.

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Written informed consent was obtained for all individual participants included in the study.

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Abdullah, I.S., Teh, SH., Khaidizar, F.D. et al. Intron retention is among six unreported AGL mutations identified in Malaysian GSD III patients. Genes Genom 41, 885–893 (2019). https://doi.org/10.1007/s13258-019-00815-9

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