Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta.
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.
Parry
David A
DA
Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK.
Mighell
Alan J
AJ
El-Sayed
Walid
W
Shore
Roger C
RC
Jalili
Ismail K
IK
Dollfus
Hélène
H
Bloch-Zupan
Agnes
A
Carlos
Roman
R
Carr
Ian M
IM
Downey
Louise M
LM
Blain
Katharine M
KM
Mansfield
David C
DC
Shahrabi
Mehdi
M
Heidari
Mansour
M
Aref
Parissa
P
Abbasi
Mohsen
M
Michaelides
Michel
M
Moore
Anthony T
AT
Kirkham
Jennifer
J
Inglehearn
Chris F
CF
D000567:Amelogenesis Imperfecta / Q000235:genetics*; D018912:Arabs / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics*; D003241:Consanguinity; D005260:Female; D006801:Humans; D008297:Male; D008877:Middle East; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology*; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000235:genetics*; D013577:Syndrome; D014071:Tooth Abnormalities / Q000235:genetics
C539261:CNNM4 protein, human; D027682:Cation Transport Proteins