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Published Online January 3, 2008
Science DOI: 10.1126/science.1151174

Reports

Submitted on October 1, 2007
Accepted on December 18, 2007

Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism

Anita Rauch 1*, Christian T. Thiel 1, Detlev Schindler 2, Ursula Wick 1, Yanick J. Crow 3, Arif B. Ekici 1, Anthonie J. van Essen 4, Timm O. Goecke 5, Lihadh Al-Gazali 6, Krystyna H. Chrzanowska 7, Christiane Zweier 1, Han G. Brunner 8, Kristin Becker 9, Cynthia J. Curry 10, Bruno Dallapiccola 11, Koenraad Devriendt 12, Arnd Dörfler 13, Esther Kinning 14, André Megarbane 15, Peter Meinecke 16, Robert K. Semple 17, Stephanie Spranger 18, Annick Toutain 19, Richard C. Trembath 20, Egbert Voß 21, Louise Wilson 22, Raoul Hennekam 23, Francis de Zegher 24, Helmut-Günther Dörr 25, André Reis 1

1 Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
2 Department of Human Genetics, University of Würzburg, Würzburg, Germany.
3 Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK.
4 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
5 Institut für Humangenetik und Anthropologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
6 Faculty of Medicine, United Arab Emirates University, Al-Ain, UAE.
7 Department of Medical Genetics, The Children’s Memorial Health Institute, Warsaw, Poland.
8 Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Netherlands.
9 North Wales Clinical Genetics Service, Glan Clwyd Hospital, Rhyl, and Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
10 Genetic Medicine Central California, Fresno, and University of California, San Franciso, California, USA.
11 IRCCS-CSS, San Giovanni Rotondo and CSS-Mendel Institute, Rome, and Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy.
12 Centre for Human-Genetics, University of Leuven, Leuven, Belgium.
13 Department of Neuroradiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
14 Department of Clinical Genetics, Leicester Royal Infirmary, Leicester, UK.
15 Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon.
16 Abteilung für Medizinische Genetik, Altonaer Kinderkrankenhaus, Hamburg, Germany.
17 Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
18 Praxis fuer Humangenetik, Bremen, Germany.
19 Department of Genetics, Bretonneau University Hospital, Tours, France.
20 Department of Medical and Molecular Genetics, School of Medicine, King’s College London, UK.
21 Cnopf’s Pediatric Hospital, Nuremberg, Germany.
22 Department of Clinical Genetics, Great Ormond Street Hospital for Children, London, UK.
23 Department of Clinical Genetics, Great Ormond Street Hospital for Children, London, UK.; Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK.; Department of Paediatrics, University of Amsterdam, Amsterdam, Netherlands.
24 Department of Woman and Child, University of Leuven, Leuven, Belgium.
25 Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.

* To whom correspondence should be addressed.
Anita Rauch , E-mail: arauch{at}humgenet.uni-erlangen.de

Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, CENPJ).


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