Alternative titles; symbols
HGNC Approved Gene Symbol: SHQ1
Cytogenetic location: 3p13 Genomic coordinates (GRCh38) : 3:72,725,272-72,848,445 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p13 | ?Dystonia 35, childhood-onset | 619921 | Autosomal recessive | 3 |
| Neurodevelopmental disorder with dystonia and seizures | 619922 | Autosomal recessive | 3 |
SHQ1 assists in the assembly of H/ACA-box ribonucleoproteins that function in the processing of ribosomal RNAs, modification of spliceosomal small nuclear RNAs, and stabilization of telomerase (see 602322) (Grozdanov et al., 2009).
Grozdanov et al. (2009) cloned human SHQ1. The deduced protein contains an N-terminal HSP20 (HSPB6; 610695)-like CS domain and a central domain that is conserved in yeast Shq1. The first 445 amino acids of yeast and human SHQ1 share 26% identity. Immunofluorescence analysis of human cell lines revealed that SHQ1 localized to the nucleoplasm in a granular pattern, with exclusion from nucleoli and Cajal bodies.
H/ACA ribonucleoproteins consist of a small nucleolar RNA (e.g., SNORA5C; 611335) and 4 core proteins: the pseudouridine synthase NAP57 (DKC1; 300126), NOP10 (NOLA3; 606471), NHP2 (NOLA2; 606470), and GAR1 (NOLA1; 606468). Using HeLa and U2OS human cell lines, Grozdanov et al. (2009) showed that SHQ1 was required for stable accumulation of all H/ACA ribonucleoproteins tested, including telomerase. SHQ1 was absent from the mature H/ACA ribonucleoproteins, consistent with its exclusion from nucleoli and Cajal bodies. Unlike all other H/ACA components, SHQ1 bound only to free NAP57 in the absence of other H/ACA proteins or RNAs. Excess recombinant SHQ1 interfered with H/ACA ribonucleoprotein assembly, apparently by sequestering endogenous NAP57. Conversely, knockdown of SHQ1 prevented accumulation of a newly synthesized H/ACA reporter RNA and generally reduced the level of endogenous H/ACA RNAs, including telomerase RNA. Grozdanov et al. (2009) hypothesized that SHQ1 functions as a NAP57 chaperone that accompanies NAP57 from the time of synthesis until its association with NOP10, NHP2, and NAF1 (617868) at the nascent H/ACA RNA.
Hartz (2010) mapped the SHQ1 gene to chromosome 3p13 based on an alignment of the SHQ1 sequence (GenBank AK001401) with the genomic sequence (GRCh37).
Childhood-Onset Dystonia 35
In 2 brothers, born of unrelated Caucasian parents (family 2), with childhood-onset dystonia-35 (DYT35; 619921), Sleiman et al. (2022) identified compound heterozygous mutations in the SHQ1 gene: a 4-bp (c.828_831del, 613663.0001 and D175Y, 613663.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. RT-PCR and Western blot analysis of patient cells showed decreased SHQ1 transcript and protein levels compared to controls. Expression of the variants in the yeast homolog (yShq1) showed that the D175Y missense variant slowed cell growth compared to controls, whereas the frameshift mutation abolished growth completely. Further in vitro functional expression studies in yeast showed that the mutation resulted in depletion of H/ACA snoRNAs and caused ribosome biogenesis defects. However, immunoprecipitation studies showed that the D175Y variant had normal interaction with Cbf5, the yeast homolog of DKC1 (300126), which corresponded to the relatively mild phenotype observed.
Neurodevelopmental Disorder with Dystonia And Seizures
In 2 sisters, born of unrelated parents of European descent (family 1) with neurodevelopmental disorder with dystonia and seizures (NEDDS; 619922), Sleiman et al. (2022) identified compound heterozygous mutations in the SHQ1 gene (c.828_831del, 613663.0001 and E292K, 613663.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. RT-PCR and Western blot analysis of patient cells showed decreased SHQ1 transcript and protein levels compared to controls. Expression of the variants in the yeast homolog (yShq1) showed that the E292K missense variant slowed cell growth compared to controls, whereas the frameshift mutation abolished growth completely. Further in vitro functional expression studies in yeast showed that the mutation resulted in depletion of H/ACA snoRNAs and caused ribosome biogenesis defects. Immunoprecipitation studies showed that the E292K variant had weakened interaction with Cbf5, the yeast homolog of DKC1 (300126). These multiple impacts on SHQ1 function corresponded to the severe phenotype observed in the patients.
In a 2-year-old male infant with spastic quadriplegia, intractable epilepsy, and cerebellar hypoplasia (NEDDS), Bizarro and Meier (2017) identified compound heterozygous missense mutations in the SHQ1 gene (R335C and A426V). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The R335C variant was found 4 times only in heterozygous state in the ExAC database; A426V was not present in ExAC. Both mutations occurred in the SSD domain, which interacts with NAP57 (DKC1; 300126), and in vitro binding studies showed that both variants reduced the binding to NAP57 (reduced to about 59% of normal values).
Dystonia-35
In 2 brothers, born of unrelated Caucasian parents (family 2), with childhood-onset dystonia-35 (DYT35; 619921), Sleiman et al. (2022) identified compound heterozygous mutations in the SHQ1 gene: a 4-bp deletion (c.828_831del, NM_018130.2), resulting in a frameshift and premature termination (Asp277SerfsTer27), and a c.523G-T transversion, resulting in an asp175-to-tyr substitution (D175Y; 613663.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. RT-PCR and Western blot analysis of patient cells showed decreased SHQ1 transcript and protein levels compared to controls. Expression of the variants in the yeast homolog (yShq1) showed that the D175Y missense variant slowed cell growth compared to controls, whereas the frameshift mutation abolished growth completely. Further in vitro functional expression studies in yeast showed that the mutation resulted in depletion of H/ACA snoRNAs and caused ribosome biogenesis defects. However, immunoprecipitation studies showed that the D175Y variant had normal interaction with Cbf5, the yeast homolog of DKC1 (300126), which corresponded to the relatively mild phenotype observed.
Neurodevelopmental Disorder with Dystonia And Seizures
In 2 sisters, born of unrelated parents of European descent (family 1) with neurodevelopmental disorder with dystonia and seizures (NEDDS; 619922), Sleiman et al. (2022) identified compound heterozygous mutations in the SHQ1 gene: c.828_831del and a c.874G-A transition, resulting in a glu292-to-lys substitution (E292K; 613663.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. RT-PCR and Western blot analysis of patient cells showed decreased SHQ1 transcript and protein levels compared to controls. Expression of the variants in the yeast homolog (yShq1) showed that the E292K missense variant slowed cell growth compared to controls, whereas the frameshift mutation abolished growth completely. Further in vitro functional expression studies in yeast showed that the E292K mutation resulted in depletion of H/ACA snoRNAs and caused ribosome biogenesis defects. Immunoprecipitation studies showed that the E292K variant had weakened interaction with Cbf5, the yeast homolog of DKC1 (300126). These multiple impacts on SHQ1 function corresponded to the severe phenotype observed in the patients.
For discussion of the c.523G-T transversion (c.523G-T, NM_018130.2) in the SHQ1 gene, resulting in an asp175-to-tyr (D175Y) substitution, that was found in compound heterozygous state in 2 sibs with childhood-onset dystonia-35 (DYT35; 619921) by Sleiman et al. (2022), see 613663.0001.
For discussion of the c.874G-A transition (c.874G-A, NM_018130.2) transversion in the SHQ1 gene, resulting in a glu292-to-lys (E292K) substitution, that was found in compound heterozygous state in 2 sibs with neurodevelopmental disorder with dystonia and seizures (NEDDS; 619922) by Sleiman et al. (2022), see 613663.0001.
Bizarro, J., Meier, U. T. Inherited SHQ1 mutations impair interaction with NAP57/dyskerin, a major target in dyskeratosis congenita. Molec. Genet. Genomic Med. 5: 805-808, 2017. [PubMed: 29178645] [Full Text: https://doi.org/10.1002/mgg3.314]
Grozdanov, P. N., Roy, S., Kuttur, N., Meier, U. T. SHQ1 is required prior to NAF1 for assembly of H/ACA small nucleolar and telomerase RNPs. RNA 15: 1188-1197, 2009. [PubMed: 19383767] [Full Text: https://doi.org/10.1261/rna.1532109]
Hartz, P. A. Personal Communication. Baltimore, Md. 12/3/2010.
Sleiman, S., Marshall, A. E., Dong, X., Mhanni, A., Alidou-D'Anjou, I., Frosk, P., Marin, S. E., Stark, Z., Del Bigio, M. R., McBride, A., Sadedin, S., Gallacher, L., Care4Rare Canada Consortium, Christodoulou, J., Boycott, K. M., Dragon, F., Kernohan, K. D. Compound heterozygous variants in SHQ1 are associated with a spectrum of neurological features, including early-onset dystonia. Hum. Molec. Genet. 31: 614-624, 2022. [PubMed: 34542157] [Full Text: https://doi.org/10.1093/hmg/ddab247]