title: Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta.
abstract: 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 positional-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 transport in visual function and biomineralization.
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Parry
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Mighell
authors.forename: Walid
authors.initials: W
authors.lastname: El-Sayed
authors.forename: Roger C
authors.initials: RC
authors.lastname: Shore
authors.forename: Ismail K
authors.initials: IK
authors.lastname: Jalili
authors.forename: Hélène
authors.initials: H
authors.lastname: Dollfus
authors.forename: Agnes
authors.initials: A
authors.lastname: Bloch-Zupan
authors.forename: Roman
authors.initials: R
authors.lastname: Carlos
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.forename: Louise M
authors.initials: LM
authors.lastname: Downey
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Blain
authors.forename: David C
authors.initials: DC
authors.lastname: Mansfield
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shahrabi
authors.forename: Mansour
authors.initials: M
authors.lastname: Heidari
authors.forename: Parissa
authors.initials: P
authors.lastname: Aref
authors.forename: Mohsen
authors.initials: M
authors.lastname: Abbasi
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kirkham
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
mesh_terms: D000567:Amelogenesis Imperfecta / Q000235:genetics*; D018912:Arabs / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics*; D003241:Consanguinity; D005260:Female; D006801:Humans; D008297:Male; D008877:Middle East; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology*; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000235:genetics*; D013577:Syndrome; D014071:Tooth Abnormalities / Q000235:genetics
chemical_list: C539261:CNNM4 protein, human; D027682:Cation Transport Proteins