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Originally published in Science Express on 3 January 2008
Science 8 February 2008:
Vol. 319. no. 5864, pp. 816 - 819
DOI: 10.1126/science.1151174
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Reports

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,22,23,24 Francis de Zegher,25 Helmuth-Günther Dörr,26 André Reis1

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, and CENPJ).

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 Francisco, CA, USA.
11 IRCCS-CSS, San Giovanni Rotondo and CSS-Mendel Institute, Rome, and Department of Experimental Medicine and Pathology, University of Rome 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 Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK.
24 Department of Paediatrics, University of Amsterdam, Amsterdam, Netherlands.
25 Department of Woman and Child, University of Leuven, Leuven, Belgium.
26 Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.

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

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The molecular landscape of ASPM mutations in primary microcephaly.
A K Nicholas, E A Swanson, J J Cox, G Karbani, S Malik, K Springell, D Hampshire, M Ahmed, J Bond, D Di Benedetto, et al. (2009)
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