Inherited SHQ1 mutations impair interaction with NAP57/dyskerin, a major target in dyskeratosis congenita

Mol Genet Genomic Med. 2017 Nov;5(6):805-808. doi: 10.1002/mgg3.314. Epub 2017 Aug 15.

Abstract

Background: The inherited bone marrow failure syndrome dyskeratosis congenita (DC) is most frequently caused by mutations in DKC1 (MIM# 300126), the gene encoding NAP57 (aka dyskerin). The typically missense mutations modulate the interaction of NAP57 with its chaperone SHQ1, but no DC mutations have been identified in SHQ1 (MIM# 613663). Here, we report on two compound heterozygous mutations in SHQ1 in a patient with a severe neurological disorder including cerebellar degeneration.

Methods: The SHQ1 mutations were identified by patient exome sequencing. The impact of the mutations was assessed in pulldown assays with recombinant NAP57.

Results: The SHQ1 mutations were the only set of mutations consistent with an autosomal recessive mode of inheritance. The mutations map to the SHQ1-NAP57 interface and impair the interaction of the recombinant SHQ1 variants with NAP57.

Conclusion: Intrauterine growth retardation and the neurological phenotype of the patient are reminiscent of the severe clinical variant of DC, the Hoyeraal-Hreidarsson syndrome (HH). Hence, SHQ1 screening may be warranted in patients with inherited bone marrow failure syndromes.

Keywords: H/ACA RNP; Hoyeraal-Hreidarsson syndrome; compound heterozygous mutations; dyskeratosis congenita; protein-protein interaction; ribonucleoprotein (RNP) biogenesis.

Publication types

  • Case Reports

MeSH terms

  • Base Sequence
  • Brain / diagnostic imaging
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • DNA Mutational Analysis
  • Dyskeratosis Congenita / diagnosis
  • Dyskeratosis Congenita / genetics*
  • Exome Sequencing
  • Humans
  • Infant
  • Intracellular Signaling Peptides and Proteins
  • Magnetic Resonance Imaging
  • Male
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Protein Binding
  • Protein Structure, Tertiary
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • NAP57
  • Nuclear Proteins
  • Recombinant Proteins
  • SHQ1 protein, human