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A homozygous variant in the beta-1,3-N-acetylglucosaminyltransferase 4 gene causes progressive brain atrophy and muscular dystrophy

European Journal of Human Genetics volume 34, pages 288–292 (2026)Cite this article

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Abstract

Protein glycosylation defects can present with early-onset brain malformations and muscular dystrophy or milder, late-onset muscular dystrophy. Here, we report a new glycosylation defect with an atypical phenotype of late-onset, progressive, severe brain atrophy and muscular dystrophy in a 47-year-old man. Exome sequencing revealed a homozygous highly deleterious c.478G>T (p.G160W) variant in the B3GNT4 gene. A knock-in mouse model replicated the patient’s muscle histology. B3GNT4 is expressed at very low levels in the thalamus, and this region was selectively preserved in the patient. The study demonstrates the first disease associated with one of the seven B3GNT galactosyltransferases and the importance of B3GNT4 in adolescence to adult muscle and CNS development.

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Fig. 1: Pedigree chart demonstrating disease and genetic affection and brain and muscle MRI findings.
Fig. 2: Histopathology and α-dystroglycan glycosylation in the muscle of the patient.
Fig. 3: The B3GNT4 G134W/G134W knock-in mouse model of the human B3GNT4 deficiency.

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Data availability

Study data are available upon request.

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Funding

The study was funded by the Danish Medical Research Council grant #7016-00095B. AT and VS are supported by the NIHR Newcastle Biomedical Research Centre. The funders had no other role than providing the funding.

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Authors and Affiliations

  1. Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    John Vissing & Thomas Krag

  2. John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK

    Ana Töpf & Volker Straub

  3. Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

    Volker Straub

Authors
  1. John Vissing
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  2. Ana Töpf
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  3. Volker Straub
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  4. Thomas Krag
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Contributions

JV, AT, VS, and TK contributed to the conception and design of the study. JV, AT, VS, and TK contributed to the acquisition and analysis of data. JV and TK contributed to drafting the text or preparing the figures.

Corresponding author

Correspondence to John Vissing.

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Competing interests

The authors declare no competing interests.

Ethical approval

The parents of the patient gave consent to all procedures, which followed institutional guidelines and were in accordance with the Helsinki declaration. The ethics committee of the Capital Region of Denmark exempted the study from normal approval as all procedures performed on the patient were part of the routine clinical workup. Genetic testing was approved by the Newcastle and North Tyneside research ethics committee (REC #09/H0906/28). Mice experiments were approved by the Danish Animal Inspectorate (permit #2019-15-0201-00286). MYO-SEQ was funded by Sanofi Genzyme, Ultragenyx, LGMD2I Research Fund, Samantha J. Brazzo Foundation, LGMD2D Foundation and Kurt+Peter Foundation, Muscular Dystrophy UK, and Coalition to Cure Calpain 3. Analysis was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900, and in part by National Human Genome Research Institute grant R01 HG009141.

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Vissing, J., Töpf, A., Straub, V. et al. A homozygous variant in the beta-1,3-N-acetylglucosaminyltransferase 4 gene causes progressive brain atrophy and muscular dystrophy. Eur J Hum Genet 34, 288–292 (2026). https://doi.org/10.1038/s41431-025-01991-x

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