TY - JOUR
T1 - THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder
AU - Broly, Martin
AU - Polevoda, Bogdan V.
AU - Awayda, Kamel M.
AU - Tong, Ning
AU - Lentini, Jenna
AU - Besnard, Thomas
AU - Deb, Wallid
AU - O'Rourke, Declan
AU - Baptista, Julia
AU - Ellard, Sian
AU - Almannai, Mohammed
AU - Hashem, Mais
AU - Abdulwahab, Ferdous
AU - Shamseldin, Hanan
AU - Al-Tala, Saeed
AU - Alkuraya, Fowzan S.
AU - Leon, Alberta
AU - van Loon, Rosa L.E.
AU - Ferlini, Alessandra
AU - Sanchini, Mariabeatrice
AU - Bigoni, Stefania
AU - Ciorba, Andrea
AU - van Bokhoven, Hans
AU - Iqbal, Zafar
AU - Al-Maawali, Almundher
AU - Al-Murshedi, Fathiya
AU - Ganesh, Anuradha
AU - Al-Mamari, Watfa
AU - Lim, Sze Chern
AU - Pais, Lynn S.
AU - Brown, Natasha
AU - Riazuddin, Saima
AU - Bézieau, Stéphane
AU - Fu, Dragony
AU - Isidor, Bertrand
AU - Cogné, Benjamin
AU - O'Connell, Mitchell R.
N1 - Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Covalent tRNA modifications play multi-faceted roles in tRNA stability, folding, and recognition, as well as the rate and fidelity of translation, and other cellular processes such as growth, development, and stress responses. Mutations in genes that are known to regulate tRNA modifications lead to a wide array of phenotypes and diseases including numerous cognitive and neurodevelopmental disorders, highlighting the critical role of tRNA modification in human disease. One such gene, THUMPD1, is involved in regulating tRNA N4-acetylcytidine modification (ac4C), and recently was proposed as a candidate gene for autosomal-recessive intellectual disability. Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1. Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities. We demonstrate that the bi-allelic variants identified cause loss of function of THUMPD1 and that this defect results in a loss of ac4C modification in small RNAs, and of individually purified tRNA-Ser-CGA. We further corroborate this effect by showing a loss of tRNA acetylation in two CRISPR-Cas9-generated THUMPD1 KO cell lines. In addition, we also show the resultant amino acid substitution that occurs in a missense THUMPD1 allele identified in an individual with compound heterozygous variants results in a marked decrease in THUMPD1 stability and RNA-binding capacity. Taken together, these results suggest that the lack of tRNA acetylation due to THUMPD1 loss of function results in a syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphism.
AB - Covalent tRNA modifications play multi-faceted roles in tRNA stability, folding, and recognition, as well as the rate and fidelity of translation, and other cellular processes such as growth, development, and stress responses. Mutations in genes that are known to regulate tRNA modifications lead to a wide array of phenotypes and diseases including numerous cognitive and neurodevelopmental disorders, highlighting the critical role of tRNA modification in human disease. One such gene, THUMPD1, is involved in regulating tRNA N4-acetylcytidine modification (ac4C), and recently was proposed as a candidate gene for autosomal-recessive intellectual disability. Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1. Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities. We demonstrate that the bi-allelic variants identified cause loss of function of THUMPD1 and that this defect results in a loss of ac4C modification in small RNAs, and of individually purified tRNA-Ser-CGA. We further corroborate this effect by showing a loss of tRNA acetylation in two CRISPR-Cas9-generated THUMPD1 KO cell lines. In addition, we also show the resultant amino acid substitution that occurs in a missense THUMPD1 allele identified in an individual with compound heterozygous variants results in a marked decrease in THUMPD1 stability and RNA-binding capacity. Taken together, these results suggest that the lack of tRNA acetylation due to THUMPD1 loss of function results in a syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphism.
KW - Acetylation
KW - Alleles
KW - Humans
KW - Intellectual Disability/genetics
KW - Mutation/genetics
KW - Neurodevelopmental Disorders/genetics
KW - RNA, Transfer/genetics
KW - RNA-Binding Proteins/genetics
KW - RNA/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85127606770&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127606770&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2022.02.001
DO - 10.1016/j.ajhg.2022.02.001
M3 - Article
C2 - 35196516
AN - SCOPUS:85127606770
SN - 0002-9297
VL - 109
SP - 587
EP - 600
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -