REPORT Mutations in CNNM4 Cause Jalili Syndrome, Consisting of Autosomal-Recessive Cone-Rod Dystrophy and Amelogenesis Imperfecta David A. Parry, 1,16 Alan J. Mighell, 1,2,16 Walid El-Sayed, 1,2 Roger C. Shore, 2 Ismail K. Jalili, 1 He ´le `ne Dollfus, 3,4 Agnes Bloch-Zupan, 5,6,7 Roman Carlos, 8 Ian M. Carr, 1 Louise M. Downey, 9 Katharine M. Blain, 10 David C. Mansfield, 11 Mehdi Shahrabi, 12 Mansour Heidari, 13 Parissa Aref, 12 Mohsen Abbasi, 12 Michel Michaelides, 14,15 Anthony T. Moore, 14,15 Jennifer Kirkham, 2 and Chris F. Inglehearn 1, * The combination of recessively inherited cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) was first reported by Jalili and Smith in 1988 in a family subsequently linked to a locus on chromosome 2q11, and it has since been reported in a second small family. We have identified five further ethnically diverse families cosegregating CRD and AI. Phenotypic characterization of teeth and visual function in the published and new families reveals a consistent syndrome in all seven families, and all link or are consistent with linkage to 2q11, confirming the existence of a genetically homogenous condition that we now propose to call Jalili syndrome. Using a posi- tional-candidate approach, we have identified mutations in the CNNM4 gene, encoding a putative metal transporter, accounting for the condition in all seven families. Nine mutations are described in all, three missense, three terminations, two large deletions, and a single base insertion. We confirmed expression of Cnnm4 in the neural retina and in ameloblasts in the developing tooth, suggesting a hitherto unknown connection between tooth biomineralization and retinal function. The identification of CNNM4 as the causative gene for Jalili syndrome, characterized by syndromic CRD with AI, has the potential to provide new insights into the roles of metal trans- port in visual function and biomineralization. Cone-rod dystrophy (CRD [MIM 120970]) usually manifests in childhood or early adulthood with predominant or equal loss of cone compared to rod photoreceptors, reduced visual acuity, color-vision abnormalities, photophobia, and visual- field loss. 1 Mutations in ABCA4 (MIM*601691), AIPL1 (MIM *604392), CRX (MIM þ602225), GUCA1A (MIM *600364), GUCY2D (MIM *600179), PITPNM3 (MIM *608921), RIMS1 (MIM *606629), SEMA4A (MIM *6072920), RPGR (MIM *312610), PROM1 (MIM *604365), and UNC119 (MIM *604011) have been associated with CRD, which can be inherited in an autosomal-dominant, autosomal- recessive, or X-linked manner (RetNet). These genes encode proteins of diverse functions, including participants in the phototransduction cascade and the visual cycle, structural components of photoreceptors, and photoreceptor-specific transcription factors. In comparison with retinal degeneration, little is under- stood about the genetic causes of abnormal tooth biominer- alization (reviewed by Bailleul-Forestier and colleagues 2,3 ). This group of conditions is traditionally considered to involve either enamel (amelogenesis imperfecta [AI] [MIM #204700]) or dentine (dentinogenesis imperfecta [DI] [MIM #125490] and dentine dysplasias [MIM %125400]), the two major hard-tissue components of teeth. Nonsyn- dromic AI has been attributed to mutations in five genes, which fall into three groups and involve the following: enamel-matrix proteins (AMELX 4 [MIM *300391]; ENAM 5 [MIM *606585]), enzymes controlling postsecretory pro- cessing of enamel-matrix proteins (KLK4 6 [MIM *603767]; MMP20 7 [MIM *604629]), and a gene of unknown function (FAM83H 8 [MIM *611927]). Only a single gene (DSPP [MIM *125485]) has been implicated in nonsyndromic DI. 9 In addition, CRD, AI, or DI can be part of syndromes involving multiple tissues and organs. CRD is a feature of some forms of Bardet Biedl syndrome (MIM 209900), Alstrom syndrome (MIM 203800), spinocerebellar ataxia type 7 (MIM 164500), and selected syndromes charac- terized by ectodermal abnormalities. AI and DI have been described as part of syndromes involving bone abnor- malities, giving insight into different forms of human 1 Leeds Institute of Molecular Medicine, University of Leeds, St. James’s University Hospital, Leeds LS9 7TF, UK; 2 Leeds Dental Institute, University of Leeds, Leeds LS2 9LU, UK; 3 AVENIR Inserm, Universite ´ de Strasbourg, 67085 Strasbourg, France; 4 Centre de re ´fe ´rence pour les affections ophtalmologiques he ´re ´di- taires (CARGO), Ho ˆpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; 5 Department of Paediatric Dentistry, Faculty of Dentistry, Louis Pasteur University, 67000 Strasbourg, France; 6 Reference Centre for Oral Manifestations of Rare Diseases, Service de Soins Bucco-Dentaires, Ho ˆpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; 7 Institute of Genetics and Molecular and Cellular Biology, Inserm, U596, CNRS, UMR7104, 67404 Illkirch Cedex, France; 8 Centro Clinico de Cabeza y Cuello, Guatemala City 01010, Guatemala; 9 Hull and East Yorkshire Eye Hospital, Hull HU3 2JZ, UK; 10 Child Dental Health, Dundee Dental Hospital, Dundee DD1 4HR, UK; 11 Department of Ophthalmology, Inverclyde Royal Hospital, Greenock PA16 0XN, UK; 12 Faculty of Dentistry, Tehran University of Medical Sciences, 1417613151 Tehran, Iran; 13 Department of Medical Genetics, Tehran University of Medical Sciences, 1417613151 Tehran, Iran; 14 Institute of Ophthalmology, University College London, London EC1V 9EL, UK; 15 Moorfields Eye Hospital, London EC1V 2PD, UK 16 These authors contributed equally to this work *Correspondence: c.inglehearn@leeds.ac.uk DOI 10.1016/j.ajhg.2009.01.009. ª2009 by The American Society of Human Genetics. 266 The American Journal of Human Genetics 84, 266–273, February 13, 2009 Open access under CC BY license.