TY - JOUR
T1 - Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness
AU - Slavotinek, Anne
AU - Misceo, Doriana
AU - Htun, Stephanie
AU - Mathisen, Linda
AU - Frengen, Eirik
AU - Foreman, Michelle
AU - Hurtig, Jennifer E.
AU - Enyenihi, Liz
AU - Sterrett, Maria C.
AU - Leung, Sara W.
AU - Schneidman-Duhovny, Dina
AU - Estrada-Veras, Juvianee
AU - Duncan, Jacque L.
AU - Haaxma, Charlotte A.
AU - Kamsteeg, Erik Jan
AU - Xia, Vivian
AU - Beleford, Daniah
AU - Si, Yue
AU - Douglas, Ganka
AU - Treidene, Hans Einar
AU - van Hoof, Ambro
AU - Fasken, Milo B.
AU - Corbett, Anita H.
N1 - Publisher Copyright:
© The Author(s) 2020. Published by Oxford University Press. All rights reserved
PY - 2020/7/1
Y1 - 2020/7/1
N2 - The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. While we ascertained five patients, three patients with distinct variants of EXOSC5 were studied in detail. The first patient had a deletion involving exons 5-6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. The additional two patients ascertained are siblings who had an early frameshift mutation in EXOSC5 and the p.Thr114Ile missense variant that were inherited in trans. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess consequences of pathogenic EXOSC5 variants. Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. These findings expand the number of genes encoding RNA exosome subunits linked to human disease while also suggesting that disease mechanism varies depending on the specific pathogenic variant.
AB - The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. While we ascertained five patients, three patients with distinct variants of EXOSC5 were studied in detail. The first patient had a deletion involving exons 5-6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. The additional two patients ascertained are siblings who had an early frameshift mutation in EXOSC5 and the p.Thr114Ile missense variant that were inherited in trans. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess consequences of pathogenic EXOSC5 variants. Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. These findings expand the number of genes encoding RNA exosome subunits linked to human disease while also suggesting that disease mechanism varies depending on the specific pathogenic variant.
UR - http://www.scopus.com/inward/record.url?scp=85089125927&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddaa108
DO - 10.1093/hmg/ddaa108
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C2 - 32504085
AN - SCOPUS:85089125927
SN - 0964-6906
VL - 29
SP - 2218
EP - 2239
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 13
ER -