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PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia

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Abstract

The glycophosphatidylinositol (GPI) anchor pathway plays an essential role in posttranslational modification of proteins to facilitate proper membrane anchoring and trafficking to lipid rafts, which is critical for many cell functions, including embryogenesis and neurogenesis. GPI biosynthesis is a multi-step process requiring the activity of over 25 distinct genes, most of them belonging to the phosphatidylinositol glycan (PIG) family and associated with rare neurodevelopmental disorders. PIGQ encodes the phosphatidylinositol glycan class Q protein and is part of the GPI-N-acetylglucosaminyltransferase complex that initiates GPI biosynthesis from phosphatidylinositol (PI) and N-acetylglucosamine (GlcNAc) on the cytoplasmic side of the endoplasmic reticulum (ER). Pathogenic variants in the PIGQ gene have been previously reported in 10 patients with congenital hypotonia, early-infantile epileptic encephalopathy, and premature death occurring in more than half cases. We detected a novel homozygous variant in PIGQ (NM_004204.5: c.1631dupA; p.Tyr544fs*79) by WES trio-analysis of a male patient with a neurodevelopmental disorder characterized by nonprogressive congenital ataxia, intellectual disability, generalized epilepsy, and cerebellar atrophy. Flow cytometry confirmed deficiency of several GPI-anchored proteins on leukocytes (CD14, FLAER). Clinical features of this case broaden the phenotypic spectrum of PIGQ-related GPI deficiency, outlining the importance of glycophosphatidylinositol (GPI) anchor pathway in the pathogenesis of cerebellar ataxia.

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Acknowledgements

We thank our patient and his parents for participating in the study.

Funding

This study was supported by Ricerca Finalizzata NET2013-02356160. GZ, FN, and EB are members of the European Reference Network for Rare Neurological Diseases (Project ID no. 739510).

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Authors and Affiliations

  1. Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    G. Zanni, F. Nicita & E. Bertini

  2. Department of Molecular Medicine, University of Pavia, Pavia, Italy

    F. D’Abrusco, V. Serpieri, R. Ciccone & E. M. Valente

  3. Unit of Diagnostic Immunology, Department of Laboratories, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    S. Cascioli, F. Corrente & R. Carsetti

  4. Child Neurology and Psychiatry Unit, University Hospital of Rome Tor Vergata, Rome, Italy

    M. Tosi

  5. Neurogenetics Research Centre, IRCCS Mondino Foundation, Pavia, Italy

    V. Serpieri & E. M. Valente

  6. Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    M. Motta

  7. Unit of Neurorehabilitation, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    G. Vasco

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  1. G. Zanni
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  2. F. D’Abrusco
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  8. R. Ciccone
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  9. M. Motta
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  10. G. Vasco
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  11. R. Carsetti
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  12. E. M. Valente
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  13. E. Bertini
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Corresponding author

Correspondence to G. Zanni.

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Ethical Approval

The study was approved by the ethics committee of IRCCS Mondino Foundation, protocol no. 20180077857.

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The authors declare no competing interests.

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Supplementary Information

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Genes in the GPI biosynthetic pathway process; associated syndromes and cerebellar phenotypes (DOC 70 KB)

12311_2021_1288_MOESM2_ESM.ppt

Cell Surface GPI-AP Levels in peripheral blood cells of the patient and controls. FLAER (proaerolysin) was used as GPI-anchored proteins marker on both neutrophils and monocytes, in combination with CD24 or CD14 on the two populations, respectively. CD58 expression was evaluated on RBC as GPI-anchored protein marker. Non-GPI-anchored proteins CD15 were applied for granulocytes identification, CD33 for monocytes and CD235a for erythrocytes (PPT 861 KB)

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Zanni, G., D’Abrusco, F., Nicita, F. et al. PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia. Cerebellum 21, 525–530 (2022). https://doi.org/10.1007/s12311-021-01288-x

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  • DOI: https://doi.org/10.1007/s12311-021-01288-x

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