IQCB1 mutations in patients with leber congenital amaurosis.
OBJECTIVE
Leber congenital amaurosis (LCA) is genetically heterogeneous, with 15 genes identified thus far, accounting for ∼70% of LCA patients. The aim of the present study was to identify new genetic causes of LCA.


METHODS
Homozygosity mapping in >150 LCA patients of worldwide origin was performed with high-density SNP microarrays to identify new disease-causing genes.


RESULTS
In three isolated LCA patients, the authors identified large homozygous regions on chromosome 3 encompassing the IQCB1 gene, which has been associated with Senior-Loken syndrome (SLSN), characterized by nephronophthisis and retinal degeneration. Mutation analysis of IQCB1 in these three patients and a subsequent cohort of 222 additional LCA patients identified frameshift and nonsense mutations in 11 patients diagnosed with LCA. On re-inspection of the patient's disease status, seven were found to have developed SLSN, but four maintained the diagnosis of LCA as the kidney function remained normal.


CONCLUSIONS
Results show that the onset of renal failure in patients with IQCB1 mutations is highly variable, and that mutations are also found in LCA patients without nephronophthisis, rendering IQCB1 a new gene for LCA. However, these patients are at high risk for developing renal failure, which in early stages is often not recognized and can cause sudden death from fluid and electrolyte imbalance. It is therefore recommended that all LCA patients be screened for IQCB1 mutations, to follow them more closely for kidney disease.
Estrada-Cuzcano
Alejandro
A
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Koenekoop
Robert K
RK
Coppieters
Frauke
F
Kohl
Susanne
S
Lopez
Irma
I
Collin
Rob W J
RW
De Baere
Elfride B W
EB
Roeleveld
Debbie
D
Marek
Jonah
J
Bernd
Antje
A
Rohrschneider
Klaus
K
van den Born
L Ingeborgh
LI
Meire
Françoise
F
Maumenee
Irene H
IH
Jacobson
Samuel G
SG
Hoyng
Carel B
CB
Zrenner
Eberhart
E
Cremers
Frans P M
FP
den Hollander
Anneke I
AI
D000293:Adolescent; D000328:Adult; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D000072661:Ciliopathies; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D005838:Genotype; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics; D057130:Leber Congenital Amaurosis / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015418:Optic Atrophies, Hereditary / Q000235:genetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
D002148:Calmodulin-Binding Proteins; D018389:Codon, Nonsense; C498171:IQCB1 protein, human