{
  "abstract": "Background The disruption of neural progenitor proliferation is a key mechanism underlying primary microcephaly, yet how cell cycle arrest leads to progenitor loss remains only partially understood. Cyclin-dependent kinases, CDK4 and CDK6, are central regulators of the G₁/S transition, but their role in cellular stress responses during neurodevelopment remains unclear.Methods We studied fibroblasts from affected individuals in two families: siblings homozygous for a CDK4 frameshift (p.Glu94Argfs*65) presenting with microcephaly and pontine hypoplasiaand a child homozygous for a CDK6 missense variant (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure.Results Loss-of-function variants in CDK4 and CDK6, core G₁/S regulators, impaired proliferation and induced mitochondrial stress responses and apoptosis. Mutant fibroblasts exhibited significantly reduced DNA synthesis and cell cycle progression, along with increased mitochondrial activity, elevated reactive oxygen species and increased apoptosis. Mitochondrial responses differed by gene: CDK4 deficiency caused mitochondrial hyperpolarisation, while CDK6 deficiency resulted in depolarisation, suggesting differences in mitochondrial apoptotic dynamics. Both variants affected mTOR pathway signalling, linking cell cycle kinase loss to disrupted metabolic regulation.Conclusion These findings uncover a previously unrecognised mitochondrial stress response accompanying proliferative failure, offering mechanistic insight into how cell cycle arrest could lead to neural progenitor depletion and brain growth disorders. More broadly, our results connect cyclin-dependent kinase dysfunction with mitochondrial homeostasis in neurodevelopment, highlighting shared pathways with neurodegeneration and cancer.",
  "authors": [
    {
      "affiliations": [
        "Pediatric Genetics, Ege University, Izmir, Turkey"
      ],
      "name": "Esra Isik"
    },
    {
      "affiliations": [
        "John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA"
      ],
      "name": "Mohammad Faraz Zafeer"
    },
    {
      "affiliations": [
        "Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida, USA"
      ],
      "name": "Guney Bademci"
    },
    {
      "affiliations": [
        "John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA"
      ],
      "name": "Memoona Ramzan"
    },
    {
      "affiliations": [
        "Department of Pediatric Genetics, Ege University, Izmir, Turkey"
      ],
      "name": "Turkan Turkut Tan"
    },
    {
      "affiliations": [
        "John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA"
      ],
      "name": "LeShon Peart"
    },
    {
      "affiliations": [
        "Department of Pediatric Genetics, Ege University, Izmir, Turkey"
      ],
      "name": "Yusuf Can Dogan"
    },
    {
      "affiliations": [
        "Department of Pediatric Genetics, Ege University, Izmir, Turkey"
      ],
      "name": "Mehmet Mert Topaloğlu"
    },
    {
      "affiliations": [
        "Pediatric Genetics, Ege University, Izmir, Turkey"
      ],
      "name": "Ozgur Cogulu"
    },
    {
      "affiliations": [
        "Department of Pediatric Hematology, Ege University, Izmir, Turkey"
      ],
      "name": "Nihal Karadas"
    },
    {
      "affiliations": [
        "Department of Pediatric Endocrinology, Ege University, Izmir, Turkey"
      ],
      "name": "Deniz O Kizilay"
    },
    {
      "affiliations": [
        "Department of Pediatric Endocrinology, Ege University, Izmir, Turkey"
      ],
      "name": "Damla Goksen"
    },
    {
      "affiliations": [
        "Department of Radiology, Ege University, Izmir, Turkey"
      ],
      "name": "Cenk Erarslan"
    },
    {
      "affiliations": [
        "Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey",
        "Ankara University Rare Diseases Application and Research Center, Ankara, Turkey"
      ],
      "name": "Duygu Duman"
    },
    {
      "affiliations": [
        "Ege Universitesi, Izmir, Turkey"
      ],
      "name": "Tahir Atik"
    },
    {
      "affiliations": [
        "John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA",
        "Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida, USA",
        "Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida, USA"
      ],
      "name": "Mustafa Tekin"
    }
  ],
  "title": "CDK4 and CDK6 variants in patients with primary microcephaly lead to cell cycle defects and mitochondria-induced apoptosis",
  "uid": "edf88202-0c13-5183-bd3a-dd2afc2eee2f"
}