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The cause of Jones syndrome put to REST: a mutation in the REST gene causes gingival fibromatosis and hearing loss

European Journal of Human Genetics volume 31, pages 377–379 (2023)Cite this article

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The Original Article was published on 13 December 2022

In 1977, Jones and coworkers reported a dominantly inherited syndrome characterized by gingival fibromatosis and progressive hearing loss [1]. The Jones study was based on the identification of affected individuals in a single family, and it was followed by descriptions of additional familial cases that were likewise characterized by co-inheritance of gingival fibromatosis and progressive hearing loss [2, 3]. Thus, Jones syndrome became recognized as a bona-fide clinical entity. However, the underlying genetic defect was not identified. In this issue of EJHG, Elisa Rahikkala and coworkers provide evidence that Jones syndrome co-segregates with heterozygosity for a frameshift mutation in the last exon of the repressor element 1 (RE1)-silencing transcription factor (REST) gene [4].

REST is a vital transcription factor. In mice, ubiquitous deletion of both Rest alleles (Rest−/−) causes upregulation of neuronal transcripts in non-neuronal cells and embryonic lethality at ~E11 [10]. Humans homozygous for loss-of-function REST mutations have not been identified; however, heterozygosity for REST mutations is now associated with the following four disorders: Wilms tumor (a childhood kidney cancer), Jones syndrome, non-syndromic gingival fibromatosis, and non-syndromic hearing loss [4, 8, 11, 12]. Based on this clinical diversity, specific groups of REST variants have been proposed to affect the molecular function of REST differently. Some of the identified pathogenic REST variants may not encode any protein product (Fig. 1B, “no protein”), others are likely to encode truncated proteins that preserve some interactions of the wild-type protein (Fig. 1B, bottom 7 variants in left column), and one of the identified variants interferes with the alternative splicing of REST (Fig. 1B, rounded bracket).

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Fig. 1: Hereditary diseases associated with pathogenic forms of REST.

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Funding

BB’s work is supported by a grant from the NIH (R01DC014953).

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Yoko Nakano & Botond Bánfi

  2. Inflammation Program, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Yoko Nakano & Botond Bánfi

  3. Department of Otolaryngology—Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Botond Bánfi

  4. Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Botond Bánfi

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  1. Yoko Nakano
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  2. Botond Bánfi
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YN and BB constructed the outline of the Comment together. BB wrote the initial draft. YN and BB edited the draft and approved the final version.

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Correspondence to Botond Bánfi.

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Nakano, Y., Bánfi, B. The cause of Jones syndrome put to REST: a mutation in the REST gene causes gingival fibromatosis and hearing loss. Eur J Hum Genet 31, 377–379 (2023). https://doi.org/10.1038/s41431-023-01292-1

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