Mutations in CNNM4 Cause Jalili Syndrome, Consisting of Autosomal Recessive Cone-Rod Dystrophy and Amelogenesis Imperfecta

Abstract

Purpose: : The combination of recessively inherited cone-rod dystrophy (CORD) and amelogenesis imperfecta (AI), a defect of tooth enamel formation, was first reported by Jalili and Smith in 1988 in a family subsequently linked to a locus on chromosome 2q11, and has since been reported in a second small family. Through identification of four further ethnically diverse families co-segregating CORD and AI this study aims to discover the underlying genetic cause and determine whether this is a phenotypically and genetically homogenous syndrome.

Methods: : Affected individuals were subject to detailed ocular and dental examinations. Ultrastructural analyses of deciduous teeth were undertaken. Microsatellite genotypes were obtained by PCR from genomic DNA and size fractionation on an ABI sequencer. SNP genotypes were obtained using Affymetrix Genome-Wide Human SNP Array 6.0. Candidate genes were amplified by PCR from genomic DNA and sequenced. Cnnm4 immunohistochemistry was performed on sections from mouse retina and demineralised rat mandible.

Results: : Phenotypic characterisation of teeth and visual function in the published and new families reveals a consistent syndrome in all six families. All link or are consistent with linkage to 2q11, confirming the existence of a genetically homogenous condition which we propose to call Jalili syndrome. Genotyping data does not reveal any large genomic deletions. Using a positional candidate approach we have identified mutations in the CNNM4 gene, encoding a putative metal transporter, accounting for the condition in all families. Eight mutations are described in all, three missense, three terminations, one 83 base pair deletion and a single base insertion. Cnnm4 immunoreactivity was observed in neural retina and ameloblasts during tooth development.

Conclusions: : We have shown Jalili syndrome, syndromic CORD with AI, is a genetically homogenous condition and identified mutations in CNNM4 as the underlying cause. Our data suggest a hitherto unknown connection between tooth biomineralisation and retinal function. Identification of CNNM4 as the causative gene has the potential to provide new insights into the roles of metal transport in visual function and biomineralisation.

Keywords: retinal degenerations: hereditary • genetics • ion transporters