RESEARCH ARTICLE Three Novel Mutations in the ANK Membrane Protein Cause Craniometaphyseal Dysplasia With Variable Conductive Hearing Loss Uwe Kornak, 1,2 Francesco Brancati, 3 Martine Le Merrer, 4 Klaske Lichtenbelt, 5 Wolfgang H€ ohne, 6 Sigrid Tinschert, 7 Francesco Giuseppe Garaci, 8,9 Bruno Dallapiccola, 3 and Peter N€ urnberg 10,11,12 * 1 Institute of Medical Genetics, Charit e Universit€ atsmedizin, Berlin, Germany 2 Max Planck Institute for Molecular Genetics, Berlin, Germany 3 IRCCS Ospedale Pediatrico Bambino Gesu `, Rome, Italy 4 INSERM U393, H^ opital Necker, Enfants Malades, Paris, France 5 Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands 6 Institut f€ ur Biochemie, Charit e – Universit€ atsmedizin Berlin, Germany 7 Institute of Clinical Genetics, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany 8 IRCCS San Raffaele Pisana, Rome, Italy 9 Department of Diagnostic Imaging and Interventional Radiology, University of Tor Vergata, Rome, Italy 10 Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany 11 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany 12 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany Received 16 December 2008; Accepted 12 December 2009 Craniometaphyseal dysplasia (CMD) is a rare, sclerosing skeletal disorder caused by mutations in ANKH, which encodes a puta- tive pyrophosphate transporting membrane protein. Six distinct ANKH mutations have been described to date. We report here on three novel mutations in simplex patients with CMD. The c.1015T>C (p.Cys339Arg) mutation found in Patient A was associated with congenital facial palsy, early-onset conductive hearing loss, and a generalized undermodeling of the long bones. The c.1172T>C (p.Leu391Pro) mutation in Patient B was asso- ciated with facial palsy, progressive conductive hearing loss, and generalized undermodeling of tubular bones. A milder pheno- type without cranial nerve affection was observed in Patient C, associated with a c.1001T>G (p.Leu334Arg) mutation. All af- fected residues lie in evolutionarily conserved sequence blocks. These additional cases and the associated mutations contribute to an improved appreciation of the variability of this rare skeletal dysplasia. Ó 2010 Wiley-Liss, Inc. Key words: craniometaphyseal dysplasia; ANKH; clinical vari- ability; novel mutations INTRODUCTION Craniometaphyseal dysplasia (CMD; OMIM 123000) is a rare sclerosing skeletal disorder characterized by skull sclerosis and hyperostosis, which can compromise cranial nerves, and reduced modeling of the femurs and other tubular bones [Gorlin et al., 1969]. Although there is evidence for an autosomal recessive variant of CMD (OMIM 218400), most cases are associated with autosomal dominant inheritance, including six distinct mutations confined to Grant sponsor: Deutsche Forschungsgemeinschaft (Collaborative Research Centre 577); Grant sponsor: Italian Ministry of Health (Ricerca Corrente 2009). *Correspondence to: Peter N€ urnberg, Cologne Center for Genomics (CCG), Universit€ at zu K€ oln, Weyertal 115b, 50931 K€ oln, Germany. E-mail: nuernberg@uni-koeln.de Published online 23 March 2010 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.a.33301 How to Cite this Article: Kornak U, Brancati F, Le Merrer M, Lichtenbelt K, H€ ohne W, Tinschert S, Garaci FG, Dallapiccola B, N€ urnberg P. 2010. Three novel mutations in the ANK membrane protein cause craniometaphyseal dysplasia with variable conductive hearing loss. Am J Med Genet Part A 152A:870–874. Ó 2010 Wiley-Liss, Inc. 870