Dental Phenotype in Jalili Syndrome Due to a c.1312 dupC Homozygous Mutation in the CNNM4 Gene

Abstract

Jalili syndrome denotes a recessively inherited combination of an eye disease (cone-rod dystrophy) and a dental disorder (amelogenesis imperfecta), which is caused by mutations in the CNNM4 gene. Whereas the ophthalmic consequences of these mutations have been studied comprehensively, the dental phenotype has obtained less attention. A defective transport of magnesium ions by the photoreceptors of the retina is assumed to account for the progressive visual impairment. Since magnesium is also incorporated in the mineral of dental hard tissues, we hypothesized that magnesium concentrations in defective enamel resulting from mutations in CNNM4 would be abnormal, if a similar deficiency of magnesium transport also accounted for the amelogenesis imperfecta. Thus, a detailed analysis of the dental hard tissues was performed in two boys of Kosovan origin affected by Jalili syndrome. Retinal dystrophy of the patients was diagnosed by a comprehensive eye examination and full-field electroretinography. A mutational analysis revealed a c.1312 dupC homozygous mutation in CNNM4, a genetic defect which had already been identified in other Kosovan families and putatively results in loss-of-function of the protein. The evaluation of six primary teeth using light and scanning electron microscopy as well as energy-dispersive X-ray spectroscopy showed that dental enamel was thin and deficient in mineral, suggesting a hypoplastic/hypomineralized type of amelogenesis imperfecta. The reduced mineral density of enamel was accompanied by decreased amounts of calcium, but significantly elevated levels of magnesium. In dentin, however, a similar mineral deficiency was associated with reduced magnesium and normal calcium levels. It is concluded that the c.1312 dupC mutation of CNNM4 results in mineralization defects of both enamel and dentin, which are associated with significantly abnormal magnesium concentrations. Thus, we could not disprove the hypothesis that a disrupted magnesium transport is involved in the development of the dental abnormalities observed in Jalili syndrome.

Intra-familial phenotype variability in patients with Jalili syndrome

“…In his phenotype dissection, Jalili described anterior open bite (AOB) in 2/30 and posterior open bite in 1/30 'type A' patients, whereas AOB was present in all three patients of the 'type B' phenotype. No open bite abnormality was seen on examination in our two patients and in one of the two patients reported by Luder et al 5 The intra-familial variability presented here is not consistent with a strict phenotype-genotype correlation, and may also argue against a rigid phenotype differentiation. 4 As the patients with 'type B' phenotype were examined at a younger age than the patient with 'type A', it is possible that those patients with 'type B' may have shown minimal macular signs as most of them had a visual impairment and signs of a cone-rod dystrophy.…”

Ultrastructural analysis of the teeth affected by amelogenesis imperfecta resulting from FAM83H mutations and review of the literature

“…We reviewed literatures regarding AI clinical phenotypes, enamel ultrastructure and the disease-causing gene mutations, and tried to establish the correlation among them (see Table II) 2,18,[20][21][22][23][24][25][26][27][28][29][30][31][32] . From the literatures review and our study, no specific correlation among the clinical phenotypes, ultrastructure and gene mutations was found for AI patients.…”

“…To date, mutations in nine genes (AMELX, CNNM4, DLX3, ENAM, FAM20A, FAM83H, KLK4, MMP20, and WDR72) have been implicated as the cause of AI [1][2][3][4][5][6][7][8] . Four genes encode enamel matrix proteins (AMELX, ENAM, MMP20, and KLK4) and the other genes encode proteins with unknown functions during amelogenesis.…”

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 mutations often take place within the conserved domains of the protein and results in loss-of-function. 16 In this study, we ascertained a large consanguineous pedigree with Jalili syndrome and described the detailed ocular and dental phenotype. Moreover, we screened CNNM4 in the patients in order to detect possible causative mutations.…”