TY - JOUR
T1 - THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder
AU - van Loon, Laura
N1 - Funding Information:
We thank participating families for their cooperation. We thank members of the O’Connell lab for helpful discussions. We thank Dr. Shalini Oberdoerffer for providing NAT10 KO HeLa cells. We thank Kevin Welle and the University of Rochester Mass Spectrometry Resource Laboratory for invaluable assistance with nucleoside mass spectrometry experiments. This work used the Typhoon RGB scanner at the Center for RNA Biology, University of Rochester, supported by the NIH S10 OD021489-01A1 instrumentation grant. M.R.O. is supported by the National Institute of General Medical Sciences grant R35GM133462 . Sequencing and analysis for subjects from family 8 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute , the National Eye Institute , and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141 .
Funding Information:
We thank participating families for their cooperation. We thank members of the O'Connell lab for helpful discussions. We thank Dr. Shalini Oberdoerffer for providing NAT10 KO HeLa cells. We thank Kevin Welle and the University of Rochester Mass Spectrometry Resource Laboratory for invaluable assistance with nucleoside mass spectrometry experiments. This work used the Typhoon RGB scanner at the Center for RNA Biology, University of Rochester, supported by the NIH S10 OD021489-01A1 instrumentation grant. M.R.O. is supported by the National Institute of General Medical Sciences grant R35GM133462. Sequencing and analysis for subjects from family 8 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. The authors declare no competing interests.
Publisher Copyright:
© 2022 American Society of Human Genetics
PY - 2022/4/7
Y1 - 2022/4/7
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 - N4-acetylcytidine
KW - NAT10
KW - RNA acetylation
KW - THUMPD1
KW - ac4C
KW - developmental disorder
KW - intellectual disability
KW - tRNA biology
KW - tRNA modifications
UR - http://www.scopus.com/inward/record.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
SN - 0002-9297
VL - 109
SP - 587
EP - 600
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -