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.

Membrane Topology and Intracellular Processing of Cyclin M2 (CNNM2)

“…Furthermore, Cnnm2 has been associated with coronary artery disease and hypertension (23)(24)(25). Finally, mutations in Cnnm4 were shown to be causative for recessive cone-rod dystrophy with amelogenesis imperfecta (26,27). In the present study, we aimed to elucidate the CNNM2 protein topology and characterize its post-translational modifications.…”

Identity-by-descent–guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy

“…10 IBD mapping has played a major role in both RD gene discovery and routine screening, combined with both Sanger sequencing and MPS. 5,11,12 In this study, we performed IBD mapping and subsequent Sanger sequencing or WES in 26 consanguineous families with a nonsyndromic (19) or syndromic (7) AR RD. In addition to a high detection rate, our approach identified conventional subtle mutations as well as a large deletion.…”

A novel mutation and variable phenotypic expression in a large consanguineous pedigree with Jalili syndrome

“…Mutations in the CNNM4 show clinical consequences, limited to retinal function and biomineralization of teeth, with CRD and AI phenotypic manifestations. 5 Deletion mutants of CNNM4, lacking the CBS (cystathionine-beta-synthase) domains, are unable to promote Mg 2+ efflux (16).…”

“…These genes encode a wide range of proteins, including the visual cycle components, structural components of photoreceptors, photoreceptor specific transcription factors, and the proteins involved in the neuronal development. 5,6 Syndromic CRD has been increasingly reported such as Bardet-Biedl, Rogers syndrome, or spinocerebellar ataxia type. 7,8 Amelogenesis imperfecta (AI) is another heterogeneous group of dental development disorders.…”

“…14,15 CNNM4 expression has been demonstrated in the enamel and dentin-forming cells, suggesting that disturbance of the Mg 2+ transport leads to mineral deficiency observed in dental enamel of AI patients. 5,7 Various kinds of mutations including missense, nonsense, deletion, and single base duplication have been identified in CNNM4 in Jalili syndrome. These mutations often take place within the conserved domains of the protein and results in loss-of-function.…”