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Evaluation of Planar-Cell-Polarity Phenotypes in Ciliopathy Mouse Mutant Cochlea
Published on: February 21, 2016
POC1A truncation mutation causes a ciliopathy in humans characterized by primordial dwarfism
Ranad Shaheen1, Eissa Faqeih, Hanan E Shamseldin
1Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia.
Insights
Primordial dwarfism (PD) is a growth disorder. A mutation in the POC1A gene causes PD by impairing cell division and cilia formation, revealing a new ciliopathy syndrome.
Area of Science:
- Genetics
- Cell Biology
- Developmental Biology
Background:
- Primordial dwarfism (PD) is a rare genetic disorder characterized by severe prenatal and postnatal growth retardation.
- Previous research has implicated various cellular processes, including mitosis, DNA repair, and gene expression, in PD pathogenesis.
Observation:
- Three families with a distinct form of PD were studied.
- A founder mutation was identified in the POC1A gene, encoding a major centriolar protein.
Findings:
- Cells from affected individuals exhibited abnormal mitotic mechanics, including multipolar spindles.
- Impaired ciliogenesis was observed, and siRNA knockdown of POC1A replicated this defect in fibroblast cells.
- The study identified a novel human ciliopathy syndrome linked to POC1A deficiency.
Implications:
- This research deepens the understanding of PD's molecular basis.
- It highlights the critical role of POC1A in human development and ciliogenesis.
- The findings suggest POC1A deficiency can cause a ciliopathy syndrome with features of primordial dwarfism.
Abstract:
Primordial dwarfism (PD) is a phenotype characterized by profound growth retardation that is prenatal in onset. Significant strides have been made in the last few years toward improved understanding of the molecular underpinning of the limited growth that characterizes the embryonic and postnatal development of PD individuals. These include impaired mitotic mechanics, abnormal IGF2 expression, perturbed DNA-damage response, defective spliceosomal machinery, and abnormal replication licensing. In three families affected by a distinct form of PD, we identified a founder truncating mutation in POC1A. This gene is one of two vertebrate paralogs of POC1, which encodes one of the most abundant proteins in the Chlamydomonas centriole proteome. Cells derived from the index individual have abnormal mitotic mechanics with multipolar spindles, in addition to clearly impaired ciliogenesis. siRNA knockdown of POC1A in fibroblast cells recapitulates this ciliogenesis defect. Our findings highlight a human ciliopathy syndrome caused by deficiency of a major centriolar protein.
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