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Biallelic hypomorphic mutations in HEATR5B, encoding HEAT repeat-containing protein 5B, in a neurological syndrome with pontocerebellar hypoplasia

European Journal of Human Genetics volume 29, pages 957–964 (2021)Cite this article

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Abstract

HEAT repeats are 37–47 amino acid flexible tandem repeat structural motifs occurring in a wide variety of eukaryotic proteins with diverse functions. Due to their ability to undergo elastic conformational changes, they often serve as scaffolds at sites of protein interactions. Here, we describe four affected children from two families presenting with pontocerebellar hypoplasia manifest clinically with neonatal seizures, severe intellectual disability, and motor delay. Whole exome sequencing identified biallelic variants at predicted splice sites in intron 31 of HEATR5B, encoding the HEAT repeat-containing protein 5B segregating in a recessive fashion. Aberrant splicing was found in patient fibroblasts, which correlated with reduced levels of HEATR5B protein. HEATR5B is expressed during brain development in human, and we failed to recover live-born homozygous Heatr5b knockout mice. Taken together, our results implicate loss of HEATR5B in pontocerebellar hypoplasia.

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Fig. 1: Clinical and genetic information for families 2610 and 3195.
Fig. 2: Pathogenic variants in HEATR5B result in mRNA intron retention.
Fig. 3: Primary dermal fibroblasts from affected member of Family 2610 show reduced HEATR5B protein level.

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Data availability

Data are available in a public, open access repository. The exome sequencing from individuals from the University of California, San Diego, study site have been deposited in the Database of Genotypes and Phenotypes under accession number dbGaP:phs000288.v2.p2. Clinvar accession IDs for this submision are: SCV001468900 and SCV001468901.

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Acknowledgements

We are indebted to the families for their participation in this study. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from: the GTEx Portal on March 3, 2018.

Funding

This work was supported by NIH grants R01NS048453 and R01NS052455 (to JGG). SGG was supported by the Ruth L. Kirschstein Institutional National Research Service Award (T32 GM008666) and from the National Institute on Deafness and Other Communication Disorders (F31HD095602). MWB was supported by an EMBO Long-Term Fellowship (ALTF 174–2015), co-funded by the Marie Curie Actions of the European Commission (LTFCOFUND2013, GA-2013–609409), and an Erwin Schrödinger Fellowship by the Austrian Science Fund (FWF, J 4197-B30). The authors thank Broad Institute (U54HG003067 to Eric Lander and UM1HG008900 to D. MacArthur) and the Yale Center for Mendelian Disorders (U54HG006504 to M. Gunel), Center for Inherited Disease Research for genotyping and sequencing support.

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Author notes

  1. Martin W. Breuss

    Present address: Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA

  2. These authors contributed equally: Shereen G. Ghosh, Martin W. Breuss

Authors and Affiliations

  1. Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA

    Shereen G. Ghosh, Martin W. Breuss, Zinayida Schlachetzki, Guoliang Chai, Danica Ross, Valentina Stanley & Joseph G. Gleeson

  2. Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA

    Shereen G. Ghosh, Martin W. Breuss, Zinayida Schlachetzki, Guoliang Chai, Danica Ross, Valentina Stanley & Joseph G. Gleeson

  3. Guven Hospital Child Neurology, Ankara, Turkey

    F. Mujgan Sonmez

  4. Department of Child Neurology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey

    F. Mujgan Sonmez

  5. Division of Pediatric Neurology, Hacettepe University Children’s Hospital, Ankara, Turkey

    Haluk Topaloglu

  6. Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt

    Maha S. Zaki & Shaimaa Gad

  7. Genetic Department, National Institution of Neuromotor Systems, Cairo, Egypt

    Heba Hosny

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  1. Shereen G. Ghosh
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Correspondence to Martin W. Breuss or Joseph G. Gleeson.

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Ghosh, S.G., Breuss, M.W., Schlachetzki, Z. et al. Biallelic hypomorphic mutations in HEATR5B, encoding HEAT repeat-containing protein 5B, in a neurological syndrome with pontocerebellar hypoplasia. Eur J Hum Genet 29, 957–964 (2021). https://doi.org/10.1038/s41431-021-00832-x

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