Alternative titles; symbols
HGNC Approved Gene Symbol: THUMPD1
Cytogenetic location: 16p12.3 Genomic coordinates (GRCh38): 16:20,733,664-20,741,818 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p12.3 | Neurodevelopmental disorder with speech delay and variable ocular anomalies | 619989 | Autosomal recessive | 3 |
THUMPD1 functions as an adaptor protein for secondary modification of transfer RNA (tRNA) by cytosine acetylation (Sharma et al., 2015).
Sharma et al. (2015) reported that the deduced 353-amino acid THUMPD1 protein has a conserved tRNA-binding THUMP domain between amino acids 111 and 254.
Sharma et al. (2015) found that overexpression of human NAT10 (609221) restored tRNA acetylation in yeast lacking the tRNA adaptor protein Tan1, the ortholog of human THUMPD1. Knockdown of NAT10 reduced tRNA acetylation in HCT116 cells. Coprecipitation analysis of HCT116 cells revealed that NAT10 interacted directly with THUMPD1. NAT10 also acetylated cytosines in 18S ribosomal RNA (see 180450) in a THUMPD1-independent manner. Sharma et al. (2015) proposed that THUMPD1 functions like Tan1 as a specific adaptor to mediate NAT10-dependent tRNA acetylation.
Hartz (2015) mapped the THUMPD1 gene to chromosome 16p12.3 based on an alignment of the THUMPD1 sequence (GenBank AK000281) with the genomic sequence (GRCh38).
In a 23-year-old man (15DG1395), born of consanguineous parents, with neurodevelopmental disorder with speech delay and variable ocular anomalies (NEDSOA; 619989), Maddirevula et al. (2019) identified a homozygous nonsense mutation in the THUMPD1 gene (Q236X; 616662.0001). The mutation, which was found by exome sequencing of a cohort of over 2,500 patients with various mendelian phenotypes, was present in the heterozygous state at a low frequency (2 x 10(-5)) in gnomAD. Functional studies of the variant and studies of patient cells were not performed.
In 13 patients from 8 unrelated families, including 2 sibs from the family reported by Maddirevula et al. (2019), Broly et al. (2022) identified homozygous or compound heterozygous mutations in the THUMPD1 gene (see, e.g., 616662.0001-616662.0005). The patients were ascertained through collaborative efforts such as the GeneMatcher Program after exome sequencing identified biallelic THUMPD1 mutations; 4 families were consanguineous. The mutations were confirmed by Sanger sequencing and demonstrated to segregate with the disorder in the 6 families from whom parental DNA was available. All were absent from or present at a low frequency in the gnomAD database. There were nonsense and frameshift mutations, 1 in-frame deletion, and 1 missense mutation (P164S) in compound heterozygous state with another loss-of-function variant. Knockdown of the THUMPD1 gene in HEK293T and HeLa cells led to a complete loss of N4-acetylcytidine (ac4C) modifications of small RNAs and tRNA(Ser), similar to that observed in cells derived from 1 patient. Broly et al. (2022) hypothesized that lack of postranscriptional tRNA acetylation due to loss of THUMPD1 function disrupts key cellular processes during neurodevelopment.
In a 23-year-old man (15DG1395), born of consanguineous parents, with neurodevelopmental disorder with speech delay and variable ocular anomalies (NEDSOA; 619989), Maddirevula et al. (2019) identified a homozygous c.706C-T transition (c.706C-T, NM_017736.3) in the THUMPD1 gene, resulting in a gln236-to-ter (Q236X) substitution. The mutation, which was found by exome sequencing of a cohort of over 2,500 patients with various mendelian phenotypes, was present in the heterozygous state at a low frequency (2 x 10(-5)) in gnomAD. Functional studies of the variant and studies of patient cells were not performed. In a follow-up study, Broly et al. (2022) found that patient 15DG1395 of Maddirevula et al., 2019 had a similarly affected brother who was homozygous for the Q236X mutation (referred to as family 2). Broly et al. (2022) also identified a homozygous Q236X mutation in an affected 8-year-old girl who was born of unrelated parents (family 3). The mutation segregated with the disorder in both families. Lymphoblastoid cells derived from 1 of the patients showed decreased THUMPD1 mRNA levels and absence of the full-length protein on Western blot analysis, suggesting that the mutant transcript is subject to nonsense-mediated mRNA decay. The mutation occurred in the second-to-last exon. Compared to controls, patient lymphoblasts showed no detectable N4-acetylcytidine (ac4C) modifications on small RNAs or tRNA(Ser). The findings were consistent with a loss of function.
In a 3.5-year-old girl, born of consanguineous parents (family 5), with neurodevelopmental disorder with speech delay and variable ocular anomalies (NEDSOA; 619989), Broly et al. (2022) identified a homozygous 4-bp deletion in the THUMPD1 gene (c.303_306del, NM_001304550.1), predicted to result in a frameshift and premature termination (Glu102LeufsTer10). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In 3 sibs, born of consanguineous parents (family 7), with neurodevelopmental disorder with speech delay and variable ocular anomalies (NEDSOA; 619989), Broly et al. (2022) identified a homozygous 3-bp in-frame deletion (c.774_776del, NM_001304550.1), predicted to result in the deletion of residue Leu258 (Leu258del). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was present at a low frequency (4 x 10(-6)) in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In 2 sibs, born of consanguineous parents (family 8), with neurodevelopmental disorder with speech delay and variable ocular anomalies (NEDSOA; 619989), Broly et al. (2022) identified a homozygous 1-bp duplication (c.634dup, NM_001304550.1) in the THUMPD1 gene, predicted to result in a frameshift and premature termination (Glu212GlyfsTer18). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In 2 brothers, born of unrelated parents (family 1), with neurodevelopmental disorder with speech delay and variable ocular anomalies (NEDSOA; 619989), Broly et al. (2022) identified a homozygous 1-bp duplication (c.495dup, NM_001304550.1) in the THUMPD1 gene, predicted to result in a frameshift and premature termination (Ser166LeufsTer24). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. However, familial segregation studies were not performed, and the mutational status of the unaffected parents was not known. Functional studies of the variant and studies of patient cells were not performed.
Broly, M., Polevoda, B. V., Awayda, K. M., Tong, N., Lentini, J., Besnard, T., Deb, W., O'Rourke, D., Baptista, J., Ellard, S., Almannai, M., Hashem, M., and 25 others. THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder. Am. J. Hum. Genet. 109: 587-600, 2022. [PubMed: 35196516] [Full Text: https://doi.org/10.1016/j.ajhg.2022.02.001]
Hartz, P. A. Personal Communication. Baltimore, Md. 11/25/2015.
Maddirevula, S., Alzahrani, F., Al-Owain, M., Al Muhaizea, M. A., Kayyali, H. R., AlHashem, A., Rahbeeni, Z., Al-Otaibi, M., Alzaidan, H. I., Balobaid, A., El Khashab, H. Y., Bubshait, D. K., and 36 others. Autozygome and high throughput confirmation of disease genes candidacy. Genet. Med. 21: 736-742, 2019. [PubMed: 30237576] [Full Text: https://doi.org/10.1038/s41436-018-0138-x]
Sharma, S., Langhendries, J.-L., Watzinger, P., Kotter, P., Entian, K.-D., Lafontaine, D. L. J. Yeast Kre33 and human NAT10 are conserved 18S rRNA cytosine acetyltransferases that modify tRNAs assisted by the adaptor Tan1/THUMPD1. Nucleic Acids Res. 43: 2242-2258, 2015. [PubMed: 25653167] [Full Text: https://doi.org/10.1093/nar/gkv075]