Hbs1 has been shown in yeast and bacterial models to play an important role in translational quality control mechanisms including non-sense mediated, non-stop and no go decay. During these processes Hbs1, through interactions with Dom34, releases stalled ribosomes from dysfunctional translation units. Ribosomal rescue is critical for normal development, organogenesis, and homeostasis and yeast lacking Hbs1 are viable but have do not grow or multiply normally. Despite this important function, the role of Hbs1L (Hbs1-like, the mammalian ortholog) in higher eukaryotes such as mice and humans is not known. Using whole exome sequencing, we have identified a patient with a paternal splice site mutation in HBS1L (chr6:135287466, c.204311G.T) and a maternal nonsense (chr6:135290431, c.1843C.T:p.R615X). The patient had severe intrauterine growth restriction, microcephaly, axial hypotonia, lax joints, global developmental delay, vertebral anomalies, cleft palate, and retinal pigmentary deposits. RT-PCR from patient fibroblasts revealed diminished HBS1L transcription and there was no Hbs1L expression on Western Blot (Fig. 1). mRNA levels of PELO, encoding for Pelota, the human ortholog of Hbs1L’s known binding partner DOM34 in yeast, were present at normal levels, however, Pelota expression was greatly diminished in the Hbs1L deficient cells (Fig. 1). Using polysome profiling, we saw that lymphoblastoid cells generated from the patient had lower levels of 80S ribosomal complexes compared with wild type cells during periods of starvation, suggesting that the Hbs1L-Pelota complex plays a role in maintaining the pool of ribosomes during times of stress. An HBS1L knock-out mouse model demonstrated similar phenotypic findings, with growth restriction, skeletal anomalies, retinal pigmentary deposits, and male factor infertility. Levels of Pelota were also decreased in mouse brain, skeletal muscle, lung, liver, spleen, and kidney, while PELO transcription was maintained at wild type levels. Overall, this data suggests that Hbs1L functions to stabilize Pelota, maintaining it for function in no-go and non-stop decay - overall maintaining of the pool of available ribosomes. This research outlines the importance of intact translational quality control mechanisms in cellular development, and this pathway holds promise as a therapeutic target for inhibiting growth of rapidly dividing cells such as in cancers.
Hbs1L mutation causes destabilization of Pelota protein and leads to growth restriction, skeletal dysplasia, retinal pigmentation, and hypotonia in humans and mice
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Amy E. O'Connell, Siqi Cao, Marie-Francoise O'Donohue, Pankaj Agrawal; Hbs1L mutation causes destabilization of Pelota protein and leads to growth restriction, skeletal dysplasia, retinal pigmentation, and hypotonia in humans and mice. Pediatrics May 2018; 142 (1_MeetingAbstract): 251. 10.1542/peds.142.1MA3.251
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