ZMYND10--Mutation Analysis in Slavic Patients with Primary Ciliary Dyskinesia

PLoS One. 2016 Jan 29;11(1):e0148067. doi: 10.1371/journal.pone.0148067. eCollection 2016.

Abstract

Primary ciliary dyskinesia (PCD) is a rare recessive disease with a prevalence of 1/10,000; its symptoms are caused by a kinetic dysfunction of motile cilia in the respiratory epithelium, flagella in spermatozoids, and primary cilia in the embryonic node. PCD is genetically heterogeneous: genotyping the already known PCD-related genes explains the genetic basis in 60-65% of the cases, depending on the population. While identification of new genes involved in PCD pathogenesis remains crucial, the search for new, population-specific mutations causative for PCD is equally important. The Slavs remain far less characterized in this respect compared to West European populations, which significantly limits diagnostic capability. The main goal of this study was to characterize the profile of causative genetic defects in one of the PCD-causing genes, ZMYND10, in the cohort of PCD patients of Slavic origin. The study was carried out using biological material from 172 unrelated PCD individuals of Polish origin, with no causative mutation found in nine major PCD genes. While none of the previously described mutations was found using the HRM-based screening, a novel frameshift mutation (c.367delC) in ZMYND10, unique for Slavic PCD population, was found in homozygous state in two unrelated PCD patients. Immunofluorescence analysis confirmed the absence of outer and inner dynein arms from the ciliary axoneme, consistent with the already published ZMYND10-mutated phenotype; cDNA analysis revealed the lack of ZMYND10 mRNA, indicating nonsense-mediated decay of the truncated transcript.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cilia / metabolism*
  • Cilia / pathology
  • Dyneins / genetics
  • Dyneins / metabolism
  • European Continental Ancestry Group
  • Female
  • Frameshift Mutation*
  • Gene Expression
  • Genes, Recessive
  • Genetic Heterogeneity
  • Homozygote
  • Humans
  • Kartagener Syndrome / ethnology*
  • Kartagener Syndrome / genetics*
  • Kartagener Syndrome / pathology
  • Male
  • Molecular Sequence Data
  • Pedigree
  • Poland
  • RNA Stability
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • RNA, Messenger
  • Tumor Suppressor Proteins
  • ZMYND10 protein, human
  • Dyneins

Grant support

The study was supported by grants from the Foundation for Polish Science to MK (International PhD Projects Programme), from the National Research Center to EZ (2011/01/B/NZ4/04840 and 2014/13/B/NZ2/03858), as well as from the European Union Seventh Framework Programme (FP7/2007-2013) funds to MW (BESTCILIA – grant agreement no. 305404). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.