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H/ACA ribonucleoprotein complex subunit 1 (Nucleolar protein family A member 1) (snoRNP protein GAR1) [NOLA1]


Pseudouridylation defect due to [i]DKC1[/i] and [i]NOP10[/i] mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis.

RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in [i]DKC1[/i], [i]NOP10[/i], or [i]NHP2[/i] cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with [i]DKC1[/i] p.Glu206Lys and two children with homozygous [i]NOP10[/i] p.Thr16Met. Females with heterozygous [i]DKC1[/i] p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin-NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin-NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish [i]dkc1[/i] mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.

MeSH Terms

  • Animals
  • Cataract
  • Cell Cycle Proteins
  • Child
  • Enterocolitis
  • Female
  • Genetic Predisposition to Disease
  • Hearing Loss, Sensorineural
  • Humans
  • Longevity
  • Male
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Mutation
  • Nephrotic Syndrome
  • Nuclear Proteins
  • Pedigree
  • Protein Conformation
  • RNA, Ribosomal
  • Ribonucleoproteins, Small Nucleolar
  • Zebrafish


  • H/ACA snoRNP
  • pediatrics
  • pseudouridylation
  • rRNA
  • telomere