Bi-allelic missense variant, p.Ser35Leu in EXOSC1 is associated with pontocerebellar hypoplasia

Somashekar, Puneeth H and Kaur, Parneet and Guleria, Vishal Singh and Rajagopal, KV and Girisha, KM and Stephen, Joshi and Upadhyai, Priyanka and Shukla, Anju (2021) Bi-allelic missense variant, p.Ser35Leu in EXOSC1 is associated with pontocerebellar hypoplasia. Clinical Genetics, 99 (4). pp. 594-600. ISSN 0009-9163

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Abstract

RNA exosome is a highly conserved ribonuclease complex essential for RNA processing and degradation. Bi-allelic variants in exosome subunits EXOSC3, EXOSC8 and EXOSC9 have been reported to cause pontocerebellar hypoplasia type 1B, type 1C and type 1D, respectively, while those in EXOSC2 cause short stature, hearing loss, retinitis pigmentosa and distinctive facies. We ascertained an 8-months-old male with developmental delay, microcephaly, subtle dysmorphism and hypotonia. Pontocerebellar hypoplasia and delayed myelination were noted on neuroimaging. A similarly affected elder sibling succumbed at the age of 4-years 6-months. Chromosomal microarray returned normal results. Exome sequencing revealed a homozygous missense variant, c.104C > T p.(Ser35Leu) in EXOSC1 (NM_016046.5) as the possible candidate. In silico mutagenesis revealed loss of a polar contact with neighboring Leu37 residue. Quantitative real-time PCR indicated no appreciable differences in EXOSC1 transcript levels. Immunoblotting and blue native PAGE revealed reduction in the EXOSC1 protein levels and EXO9 complex in the proband, respectively. We herein report an individual with the bi-allelic variant c.104C>T p.(Ser35Leu) in EXOSC1 and clinical features of pontocerebellar hypoplasia type 1. Immunoblotting and blue native PAGE provide evidence for the pathogenicity of the variant. Thus, we propose EXOSC1 as a novel candidate gene for pontocerebellar hypoplasia.

Item Type: Article
Uncontrolled Keywords: Blue native PAGE; EXOSC1; pontocerebellar hypoplasia; RNA exosome.
Subjects: Medicine > KMC Manipal > Medical Genetics
Medicine > KMC Manipal > Radiology
Depositing User: KMC Library
Date Deposited: 01 Jun 2021 09:01
Last Modified: 12 May 2022 04:52
URI: http://eprints.manipal.edu/id/eprint/156717

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