期刊
EUROPEAN JOURNAL OF HUMAN GENETICS
卷 29, 期 6, 页码 957-964出版社
SPRINGERNATURE
DOI: 10.1038/s41431-021-00832-x
关键词
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资金
- NIH [R01NS048453, R01NS052455]
- Ruth L. Kirschstein Institutional National Research Service Award [T32 GM008666]
- National Institute on Deafness and Other Communication Disorders [F31HD095602]
- EMBO Long-Term Fellowship [ALTF 174-2015]
- Marie Curie Actions of the European Commission [LTFCOFUND2013, GA-2013-609409]
- Austrian Science Fund (FWF) [J 4197-B30]
- Broad Institute [U54HG003067, UM1HG008900]
- Yale Center for Mendelian Disorders [U54HG006504]
HEAT repeats are flexible tandem repeat structural motifs found in a variety of eukaryotic proteins, serving as scaffolds at protein interaction sites. Loss of HEATR5B due to genetic mutations may be associated with pontocerebellar hypoplasia, characterized by neonatal seizures, severe intellectual disability, and motor delay.
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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