DKC1

Gene Facts

• HGNC Symbol: DKC1 (HGNC:2890)
• HGNC Name: dyskerin pseudouridine synthase 1
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: DKC
• Alias symbols: XAP101, dyskerin, NAP57, NOLA4, Cbf5
• %HI: 6.32
• pLI: 1
• LOEUF: 0.19
• Cytoband: Xq28
• Genomic Coordinates:

  GRCh37/hg19:	chrX:153991139-154005964
  GRCh38/hg38:	chrX:154762864-154777689

• MANE Select Transcript: NM_001363.5 ENST00000369550.10
• Function: [Isoform 1]: Catalytic subunit of H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA (PubMed:25219674, PubMed:32554502). This involves the isomerization of uridine such that the ribose is subsequently attached to C5, instead of the normal N1 (PubMed:25219674). Each rRNA can contain up to 100 pseudouridine ('psi') residues, which may serve to stabilize the conformation of rRNAs. Required for ribosome biogenesis and telomere maintenance (PubMe... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-32029
• ClinGen Curation ID: CCID:006994
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 06/14/2023

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Disease

• DKC1-related disorder

HI Evidence

• PUBMED: 18627054
  Pearson (2008): A report of a male patient with Hoyeraal-Hreidarsson syndrome (a severe form of dyskeratosis congenita) who had a DKC1 variant identified at IVS12+1 which resulted in a retention of intron 12 and a premature truncation. This variant was found in the patient's unaffected carrier mother.

• HI Evidence Comments: Many mutations in DKC1 have been described in patients with X-linked dyskeratosis congenita. However, the vast majority of these are missense variants. The exceptions to this include the patient described above by Pearson et al. as well as one patient with a 2 kb deletion that partially overlaps the 3' end of DKC1 (normal transcription was observed), PMID: 9590285 and 10438713. There have not been any variants described that clearly indicate that loss of function is a mechanism of disease. Animal model studies showed that large deletion lacking exons 12-15 and a small deletion lacking only the last exon could cause 100% embryonic lethality when the mutation occurred on the maternal Dkc1 in mice. (PMID: 12400016). Additional literatures with missense variants include PMIDs 10700698, 21931702, 10583221, 10364516, 29483670, 24914498.

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.