Biallelic hypomorphic mutations in HEATR5B, encoding HEAT repeat-containing protein 5B, in a neurological syndrome with pontocerebellar hypoplasia
Year: 2021
Type: article
Study design: Case Report
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.
Institutions: University of California San Diego, Rady Children's Institute for Genomic Medicine, University of Colorado Anschutz, University of Colorado Denver, Karadeniz Technical University, Hacettepe University Hospital, Hacettepe University, National Research Centre, The National Institute of Neuromotor System
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,380
Funders: U.S. Department of Health and Human Services, European Molecular Biology Organization, Yale University, Broad Institute, European Commission, Austrian Science Fund, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute on Deafness and Other Communication Disorders, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Common Fund
Awards: G1044130170, G1144034121, G1565454821, G1609525565, G1610708064, G1718306089, Molecular Characterization of Joubert Syndrome, G2545145014, G2736151378, G2795716607, G3245471538, Direct Quantification of Germline Mosaicism in Humans, G4302627264, Jouberin and Nephrocystin in Joubert Syndrome, Supporting transnational mobility within the European life sciences by cofunding of the EMBO Fellowship Programme, G5183736941, Molecular mechanisms of the ADPRHL2-mediated pediatric neurodegenerative disease, G7290764386, G770899802, G8849460995, G9000022338, G9000030805, G9000045419, G9000124804, G9000195759, G9000218430, Yale Clinical and Translational Science Award
OpenAlex ID: W3151848438