Pontocerebellar Hypoplasia Associated With p.Arg183Trp Homozygous Variant in EXOSC1 Gene: A Case Report

Authors

Nadirah S Damseh
Ali N Obeidat
Khondakar Sayef Ahammed
Motee Al-Ashhab
Motee Abu Awad
Ambro van Hoof

Publication Date

7-1-2023

Journal

American Journal of Medical Genetics

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.

Keywords

Humans, Female, Infant, Microcephaly, Cerebellar Diseases, Olivopontocerebellar Atrophies, Mutation, Nervous System Malformations, Exosome Multienzyme Ribonuclease Complex, RNA-Binding Proteins, Pontocerebellar hypoplasia type 1, EXOSC1, dilated cardiomyopathy, exosomopathy

Comments

PMID: 37024942