Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1

Abstract

We investigated an Amish family in which three siblings presented with an early-onset childhood retinal dystrophy inherited in an autosomal recessive fashion. Genome-wide linkage analysis identified significant linkage to marker D2S2216 on 2q11 with a two-point LOD score of 1.95 and a multi-point LOD score of 3.76. Whole exome sequencing was then performed for the three affected individuals and identified a homozygous nonsense mutation (c.C1813T, p.R605X) in the cyclin and CBS domain divalent metal cation transport mediator 4 (CNNM4) gene located within the 2p14-2q14 Jalili syndrome locus. The initial assessment and collection of the family were performed before the clinical delineation of Jalili syndrome. Another assessment was made after the discovery of the responsible gene and the dental abnormalities characteristic of Jalili syndrome were retrospectively identified. The p.R605X mutation represents the first probable founder mutation of Jalili syndrome identified in the Amish community. The molecular mechanism underlying Jalili syndrome is unknown. Here we show that CNNM4 interacts with IQCB1, which causes Leber congenital amaurosis (LCA) when mutated. A truncated CNNM4 protein starting at R605 significantly increased the rate of apoptosis, and significantly increased the interaction between CNNM4 and IQCB1. Mutation p.R605X may cause Jalili syndrome by a nonsense-mediated decay mechanism, affecting the function of IQCB1 and apoptosis, or both. Our data, for the first time, functionally link Jalili syndrome gene CNNM4 to LCA gene IQCB1, providing important insights into the molecular pathogenic mechanism of retinal dystrophy in Jalili syndrome.

Significant association of rare variant p.Gly8Ser in cardiac sodium channel β4‐subunit SCN4B with atrial fibrillation

“…Highly sensitive high-resolution melt (HRM) analysis was used for mutational analysis using DNA samples from a panel of 477 AF patients as described (Li et al, 2018; Wang et al, 2016). All exons and exon–intron boundaries were amplified using polymerase chain reactions using the primers listed in Supplementary Table S1.…”

“…DNA sequencing analysis was performed using a BigDye Terminator Cycle Sequencing Kit by Shanghai Sangni Biotechnology (Applied Biosystems, Foster City, CA) as described (Li et al, 2018; Wang et al, 2016). Sequencing data were directly viewed using Sequencing Analysis (version 5.1.1, Applied Biosystems) to identify potential variants.…”

Novel homozygous nonsynonymous variant of CNNM4 gene in a Chinese family with Jalili syndrome

“…Based on the fundus appearance, it is obvious that the patients in our study belonged to type-A JS. Furthermore, the atrophic macula and macular coloboma seemed more severe compared with other type-A JS patients reported in previous literatures (Cherkaoui Jaouad et al, 2017;Jalili, 2010;Li et al, 2018). Currently, no genotypic correlations have been identified between these two distinct clinical types (Hirji et al, 2018;Jalili, 2010).…”

Physiological and oncogenic roles of the PRL phosphatases

“…As for the last member of this subfamily, CNNM4 was found at the plasma membrane and was observed to stimulate Mg 2+ /Na + exchange [184,191,204,205]. Genome-wide studies identified mutations in several patients, which resulted in a truncated CNNM4 protein, causing recessive cone-rod dystrophy and amelogenesis imperfecta, termed as Jalili syndrome [206][207][208]. Interestingly, hypomineralization of the tooth enamel was also observed when CNNM4 was knocked out in mice, supporting its role in cation transport and its link with amelogenesis imperfecta [204].…”