Novel compound heterozygous variants in PLK4 identified in a patient with autosomal recessive microcephaly and chorioretinopathy

Eur J Hum Genet. 2016 Dec;24(12):1702-1706. doi: 10.1038/ejhg.2016.119. Epub 2016 Sep 21.

Abstract

It has been well documented that variants in genes encoding centrosomal proteins cause primary autosomal recessive microcephaly, although the association between centrosomal defects and the etiology of microcephaly syndromes is not fully understood. Polo-like kinase 4 (PLK4) is one of the centrosomal proteins required for centriole duplication. We here describe a patient with microcephaly and chorioretinopathy that harbors compound heterozygous missense variants, c.[442A>G]; [2336G>A], in the PLK4 gene. One of these variants, c.442A>G (p.(M148V)), resides in the kinase domain, and the other, c.2336G>A (p.(C779Y)), in the polo-box domain. Aberrant spindle formation was observed in a LCL derived from this patient. Overexpression experiments of the variant PLK4 proteins demonstrated that the p.(C779Y) but not the p.(M148V) had lost centriole overduplication ability. The altered mobility pattern of both variant proteins on a western blot further suggested alterations in post-translation modification. Our data lend support to the hypothesis that impaired centriole duplication caused by PLK4 variants may be involved in the etiology of microcephaly disorder.

MeSH terms

  • Centrioles / metabolism
  • Centrioles / pathology
  • Choroid Diseases / diagnosis
  • Choroid Diseases / genetics*
  • Choroid Diseases / metabolism
  • Eye Diseases, Hereditary / diagnosis
  • Eye Diseases, Hereditary / genetics*
  • Eye Diseases, Hereditary / metabolism
  • Female
  • HeLa Cells
  • Heterozygote*
  • Humans
  • Infant, Newborn
  • Microcephaly / diagnosis
  • Microcephaly / genetics*
  • Microcephaly / metabolism
  • Mutation, Missense*
  • Protein Processing, Post-Translational
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Retinal Diseases / diagnosis
  • Retinal Diseases / genetics*
  • Retinal Diseases / metabolism

Substances

  • PLK4 protein, human
  • Protein Serine-Threonine Kinases

Supplementary concepts

  • Microcephaly with Chorioretinopathy, Autosomal Recessive