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A loss of function variant in AGPAT3 underlies intellectual disability and retinitis pigmentosa (IDRP) syndrome

European Journal of Human Genetics volume 31, pages 1447–1454 (2023)Cite this article

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Abstract

Intellectual disability (ID) and retinal dystrophy (RD) are the frequently found features of multiple syndromes involving additional systemic manifestations. Here, we studied a family with four members presenting severe ID and retinitis pigmentosa (RP). Using genome wide genotyping and exome sequencing, we identified a nonsense variant c.747 C > A (p.Tyr249Ter) in exon 7 of AGPAT3 which co-segregates with the disease phenotype. Western blot analysis of overexpressed WT and mutant AGPAT3 in HEK293T cells showed the absence of AGPAT3, suggesting instability of the truncated protein. Knockdown of Agpat3 in the embryonic mouse brain caused marked deficits in neuronal migration, strongly suggesting that reduced expression of AGPAT3 affects neuronal function. Altogether, our data indicates that AGPAT3 activity is essential for neuronal functioning and loss of its activity probably causes intellectual disability and retinitis pigmentosa (IDRP) syndrome.

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Fig. 1: Pedigree and clinical information of family with IRDP syndrome.
Fig. 2: Map of chromosome 21 showing location of AGPAT3 gene.
Fig. 3: AGPAT3 overexpression and knockdown.

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Data availability

Data generated during the study are available from corresponding author on reasonable request. The variant information has been deposited in Clinvar with submission ID SCV 003929458.

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Acknowledgements

We acknowledge the volunteer participation of patients and other members of the family. We are thankful to the Higher Education Commission of Pakistan for providing International Research Support Fellowship to Madiha Amin Malik. Deborah A Nickerson made significant contributions to the work. Dr. Nickerson was a very distinguished and highly respected researcher who passed away too early. Therefore, we acknowledge her work and the impact that she and her research activities are still making. We are also thankful to University of Washington Center for Mendelian Genomics for their support in the exome sequencing.

Funding

The research was supported by National Research Grant (NRPU-7099) to Muhammad Ansar by Higher Education Commission of Pakistan, International Research Support Fellowship (IRSIP) to Madiha Amin Malik by Higher Education Commission of Pakistan and by the National Institute of Health – National Institute of Child Health and Development grant R01 HD109342 to Suzanne M. Leal.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan

    Madiha Amin Malik, Muhammad Rizwan Alam & Muhammad Ansar

  2. Department of Neuroscience, Erasmus University Medical Center, Rotterdam, The Netherlands

    Madiha Amin Malik, Edwin Mientjes, Ilse Wallaard & Ype Elgersma

  3. Department of Medical Laboratory Technology, National Skills University, Islamabad, 44000, Pakistan

    Muhammad Arif Nadeem Saqib

  4. Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY, USA

    Anushree Acharya, Isabelle Schrauwen & Suzanne M. Leal

  5. Department of Genome Sciences, University of Washington, William H. Foege Hall, 3720 15th Ave. NE, Seattle, WA, 98195, USA

    Michael J. Bamshad

  6. Department of Pediatrics, University of Washington, Seattle, WA, USA

    Michael J. Bamshad

  7. Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus (CU-AMC), 12700 E. 19th Ave, Aurora, CO, 80045, USA

    Regie Lyn P. Santos-Cortez

  8. Taub Institute for Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA

    Suzanne M. Leal

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  1. Madiha Amin Malik
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Contributions

Conceptualization and study design: MAM, YE, SML, MA; Family recruitment and clinical tests: MANS; Homozygosity mapping (HB) and exome sequencing (ES): AA, IS, MJB, RLPS-C; HB and ES data analysis: MAM, MANS, AA, RLPS-C; AGPAT3 constructs and western blotting (WB) experiments and data analysis: MAM, EM; In utero electroporation (IUE) experiments: MAM, IW; IUE data analysis: MAM; First draft of manuscript: MAM, IS, SML, MA: Manuscript review and editing: MAM, EM, MRA, YE, SML, MA. All co-authors read and approved the manuscript.

Corresponding authors

Correspondence to Suzanne M. Leal or Muhammad Ansar.

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The authors declare no competing interests.

Ethical approval

It is certified that the study was performed in accordance with the ethical standards of 1964 Helsinki Declaration. The study was conducted by obtaining ethical approval from Bio-Ethics Committee (BEC-562) of Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan and Institutional Review Board (IRB), at Columbia University (IRB-AAAS3433), USA. Animal experiments were performed in accordance with European Commission Council Directive 2010/63/EU (CCD approval AVD101002017893) at Erasmus Medical Center, Rotterdam, Netherlands.

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Malik, M.A., Saqib, M.A.N., Mientjes, E. et al. A loss of function variant in AGPAT3 underlies intellectual disability and retinitis pigmentosa (IDRP) syndrome. Eur J Hum Genet 31, 1447–1454 (2023). https://doi.org/10.1038/s41431-023-01475-w

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