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Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle and ciliary defects

Jillian P Casey1, Kieran Brennan2, Noemie Scheidel2

  • 1Clinical Genetics, Children's University Hospital, Temple Street, Dublin 1, Ireland, UCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, jillian.casey@ucd.ie.

Human Molecular Genetics
|February 25, 2016
PubMed

Insights

A novel lethal skeletal dysplasia, a previously uncharacterized disorder affecting bone and cartilage, has been identified. This condition is caused by a mutation in the NEK9 gene, impacting cell division and potentially cilia function.

Area of Science:

  • Genetics
  • Cell Biology
  • Developmental Biology

Background:

  • Skeletal dysplasias are a diverse group of bone and cartilage disorders, with a significant portion remaining genetically uncharacterized.
  • Over 450 skeletal dysplasias are known, highlighting the complexity of skeletal development and the need for genetic identification.

Purpose of the Study:

  • To identify the genetic cause of a previously undescribed lethal skeletal dysplasia in two Irish Traveller families.
  • To characterize the clinical and molecular features of this novel disorder and investigate the function of the identified gene.

Main Methods:

  • Whole exome sequencing and SNP homozygosity mapping were used to identify the genetic mutation.
  • NEK9 protein expression, localization, and cellular functions (proliferation, cell cycle) were analyzed in patient fibroblasts.
  • Cilia number and length were assessed in patient cells, and NEK9 orthologue function was examined in C. elegans.

Main Results:

  • A novel homozygous stop-gain mutation (c.1489C>T; p.Arg497*) in the NEK9 gene was identified as the cause of the lethal skeletal dysplasia.
  • Patient fibroblasts exhibited a complete loss of full-length NEK9, reduced cell proliferation, and delayed cell cycle progression.
  • Patient cells showed reduced cilia number and length, and the NEK9 orthologue in C. elegans (nekl-1) is expressed in ciliated cells, suggesting a role in cilia function.

Conclusions:

  • This study reports the first human disorder associated with the NEK9 gene, a lethal skeletal dysplasia.
  • The findings suggest that NEK9 plays a critical role in skeletal development, cell cycle regulation, and potentially ciliogenesis.
  • This newly identified skeletal dysplasia may represent a novel ciliopathy, expanding the spectrum of NEK9-related disorders.

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