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

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.

Automated summary

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.