Mutations in PIH1D3 Cause X-Linked Primary Ciliary Dyskinesia with Outer and Inner Dynein Arm Defects

Am J Hum Genet. 2017 Jan 5;100(1):160-168. doi: 10.1016/j.ajhg.2016.11.019.

Tamara Paff ¹, Niki T Loges ², Isabella Aprea ², Kaman Wu ³, Zeineb Bakey ³, Eric G Haarman ⁴, Johannes M A Daniels ⁵, Erik A Sistermans ⁶, Natalija Bogunovic ⁷, Gerard W Dougherty ², Inga M Höben ², Jörg Große-Onnebrink ², Anja Matter ², Heike Olbrich ², Claudius Werner ², Gerard Pals ⁶, Miriam Schmidts ⁸, Heymut Omran ², Dimitra Micha ⁹

Affiliations

1 Department of Pulmonary Diseases, VU University Medical Center, 1007 MB Amsterdam, the Netherlands; Department of Paediatric Pulmonology, VU University Medical Center, 1007 MB Amsterdam, the Netherlands; Department of Clinical Genetics, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
2 Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
3 Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, the Netherlands.
4 Department of Paediatric Pulmonology, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
5 Department of Pulmonary Diseases, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
6 Department of Clinical Genetics, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
7 Department of Surgery and Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
8 Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, the Netherlands; Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, 79110 Freiburg, Germany.
9 Department of Clinical Genetics, VU University Medical Center, 1007 MB Amsterdam, the Netherlands. Electronic address: d.micha@vumc.nl.

PMID: 28041644 DOI: 10.1016/j.ajhg.2016.11.019

Abstract

Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right body axis disturbance. Here we report maternally inherited and de novo mutations in PIH1D3 in four men affected with PCD. PIH1D3 is located on the X chromosome and is involved in the preassembly of both outer (ODA) and inner (IDA) dynein arms of cilia and sperm flagella. Loss-of-function mutations in PIH1D3 lead to absent ODAs and reduced to absent IDAs, causing ciliary and flagellar immotility. Further, PIH1D3 interacts and co-precipitates with cytoplasmic ODA/IDA assembly factors DNAAF2 and DNAAF4. This result has clinical and genetic counseling implications for genetically unsolved male case subjects with a classic PCD phenotype that lack additional phenotypes such as intellectual disability or retinitis pigmentosa.

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