Pontocerebellar hypoplasia associated with p.Arg183Trp homozygous variant in EXOSC1 gene: A case report

Abstract

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders characterized by a wide phenotypic range including severe motor and cognitive impairments, microcephaly, distinctive facial features, and other features according to the type. Several classes of PCH1 have been linked to mutations in the evolutionarily conserved RNA exosome complex that consists of nine subunits (EXOSC1 to EXOSC9) and facilitates the degradation and processing of cytoplasmic and nuclear RNA from the 3′ end. Only a single individual with an EXOSC1 mutation was reported with clinical features of PCH type 1 (PCH1F). Here, we report a 3‐month‐old female with PCH and additional clinical features not previously reported to be associated with PCH1, including dilated cardiomyopathy. On assessment, failure to thrive, microcephaly, distinctive facial features, and bluish sclera, were noted. Whole‐exome sequencing was performed and revealed a novel homozygous missense variant c.547C > T (p.Arg183Trp) in the EXOSC1 gene. Functional studies in a budding yeast model that expresses the human EXOSC1 variant Arg183Trp show a slow‐growth phenotype, whereas the previously identified PCH1F allele EXOSC1‐Ser35Leu is lethal, indicating impaired exosome function for both of these variants. The protein levels of both EXOSC1 variants are reduced compared with wild‐type when expressed in budding yeast. Herein, we ascertain the second case of PCH associated with a EXOSC1 variant that causes defects in RNA exosome function and provide a model organism system to distinguish between benign and pathogenic variants in EXOSC1.

A Biallelic Variant of the RNA Exosome GeneEXOSC4Causes Translational Defects Associated with a Neurodevelopmental Disorder

“…This work adds the EXOSC4 gene to a growing list of genes that are linked clinically to a class of syndromes termed exosomopathies. Consistent with many of the exosomopathies reported thus far (8, 14), the pathogenic mutation identified in EXOSC4 (p.L187P) causes a single amino acid change in an evolutionary conserved sequence within EXOSC4. Modeling of this pathogenic amino acid substitution in the budding yeast protein corresponding to EXOSC4, Rrp41, reveals that cells which express the Rrp41-L187P variant as the sole copy of the essential Rrp41 protein show severe growth defects as well as accumulation of a number of RNA exosome target transcripts, including 7S pre-rRNA.…”

“…This work adds the EXOSC4 gene to a growing list of genes that are linked clinically to a class of syndromes termed exosomopathies. Consistent with many of the exosomopathies reported thus far (8,14), the pathogenic mutation identified in EXOSC4 (p.L187P) causes a single amino . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.…”

“…The initial finding was that mutations within the EXOSC3 gene, which encodes one of the cap subunits, are linked to pontocerebellar hypoplasia type 1B (PCH1b) (6). Subsequent studies have led to the identification of a number of additional pathogenic mutations in EXOSC3 (7) as well as mutations in EXOSC1, 2, 5, 8, and 9 that have been linked to autosomal recessive disease (8)(9)(10)(11)(12)(13). The majority of the pathogenic mutations identified in EXOSC genes cause single amino acid substitutions.…”