A study in pleiotropy – Jalili syndrome

Abstract

Jalili syndrome, first described 25 years ago in a Palestinian family, is a rare autosomal recessive genetic disorder that is characterized by the comorbid appearance of cone–rod dystrophy (CRD) and amelogenesis imperfecta. To date, 71 patients with this condition belonging to 17 different families have been reported worldwide. Studies into the molecular aetiology of Jalili syndrome have identified mutations in the CNNM4 gene, located on chromosome 2q11. Other members of this protein family have been shown to be involved in mineral transport. We postulate a role for the CNNM4 protein in metal ion transport and homeostasis and especially in the transport of magnesium ions. Mutations in the gene could interfere with the depolarization process of retinal cells, as well as in the dental biomineralization process. We also show that mutations localized to the transmembrane domain of this protein result in more severe phenotypes of the syndrome, indicating an important function for this domain, probably as a transmembrane channel for metal transport. Jalili syndrome offers an example of how a single mutation in a gene is capable of affecting two independent traits by causing a defect in a single protein that carries out essentially the same function in two different tissue types. Given that 274 inherited disorders, almost exclusively reported in Arab families, have no defined genetic aetiologies as yet, and with the increasing trend of genome-wide association studies in the region, it is highly plausible that more conditions will be assumed to be manifestations of pleiotropy.