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

Autor: Damseh NS; Department of Pediatrics and Genetics, Al Makassed Hospital, East Jerusalem, Palestine.; Faculty of Medicine, Al-Quds University, Abu Deis, Palestine., Obeidat AN; Faculty of Medicine, Al-Quds University, Abu Deis, Palestine., Ahammed KS; Department of Microbiology and Molecular Genetics, University of Texas Health Science Center at Houston, Houston, Texas, USA.; MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, Texas, USA., Al-Ashhab M; Department of Pediatrics and Genetics, Al Makassed Hospital, East Jerusalem, Palestine.; Faculty of Medicine, Al-Quds University, Abu Deis, Palestine., Awad MA; Department of Pediatrics and Genetics, Al Makassed Hospital, East Jerusalem, Palestine.; Faculty of Medicine, Al-Quds University, Abu Deis, Palestine., van Hoof A; Department of Microbiology and Molecular Genetics, University of Texas Health Science Center at Houston, Houston, Texas, USA.; MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, Texas, USA.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2023 Jul; Vol. 191 (7), pp. 1923-1928. Date of Electronic Publication: 2023 Apr 06.
DOI: 10.1002/ajmg.a.63198
Abstrakt: 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.
(© 2023 Wiley Periodicals LLC.)
Databáze: MEDLINE
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