2. Academic Validation
  3. Novel compound heterozygous variants in PLK4 identified in a patient with autosomal recessive microcephaly and chorioretinopathy

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.
Makiko Tsutsumi 1,  Setsuri Yokoi 1 2,  Fuyuki Miya 3 4,  Masafumi Miyata 5,  Mitsuhiro Kato 6,  Nobuhiko Okamoto 7,  Tatsuhiko Tsunoda 3 4,  Mami Yamasaki 8,  Yonehiro Kanemura 9 10,  Kenjiro Kosaki 11,  Shinji Saitoh 12,  Hiroki Kurahashi 1
Affiliations

Affiliations

  • 1 Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan.
  • 2 Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 3 Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
  • 4 Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • 5 Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan.
  • 6 Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan.
  • 7 Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
  • 8 Department of Pediatric Neurosurgery, Takatsuki General Hospital, Osaka, Japan.
  • 9 Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan.
  • 10 Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan.
  • 11 Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
  • 12 Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
PMID: 27650967 DOI: 10.1038/ejhg.2016.119
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.

Figures