A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome.
BACKGROUND
Usher syndrome (USH) is a heterogeneous group of inherited retinitis pigmentosa (RP) and sensorineural hearing loss (SNHL) caused by mutations in at least 12 genes. Our aim is to identify additional USH-related genes.


METHODS
Clinical examination included visual acuity test, funduscopy and electroretinography. Genetic analysis included homozygosity mapping and whole exome sequencing (WES).


RESULTS
A combination of homozygosity mapping and WES in a large consanguineous family of Iranian Jewish origin revealed nonsense mutations in two ciliary genes: c.3289C>T (p.Q1097*) in C2orf71 and c.3463C>T (p.R1155*) in centrosome-associated protein CEP250 (C-Nap1). The latter has not been associated with any inherited disease and the c.3463C>T mutation was absent in control chromosomes. Patients who were double homozygotes had SNHL accompanied by early-onset and severe RP, while patients who were homozygous for the CEP250 mutation and carried a single mutant C2orf71 allele had SNHL with mild retinal degeneration. No ciliary structural abnormalities in the respiratory system were evident by electron microscopy analysis. CEP250 expression analysis of the mutant allele revealed the generation of a truncated protein lacking the NEK2-phosphorylation region.


CONCLUSIONS
A homozygous nonsense CEP250 mutation, in combination with a heterozygous C2orf71 nonsense mutation, causes an atypical form of USH, characterised by early-onset SNHL and a relatively mild RP. The severe retinal involvement in the double homozygotes indicates an additive effect caused by nonsense mutations in genes encoding ciliary proteins.
Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Samer
S
Khateb
Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Lina
L
Zelinger
Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Liliana
L
Mizrahi-Meissonnier
Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), CIBERER, ISCIII, Madrid, Spain.
Carmen
C
Ayuso
Departments of Human Genetics, Paediatric Surgery and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.
Robert K
RK
Koenekoop
Department of Pulmonology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Uri
U
Laxer
Department of Otolaryngology, Head and Neck Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Menachem
M
Gross
Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Eyal
E
Banin
Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Dror
D
Sharon
D001324:Autoantigens / Q000235:genetics*; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D018389:Codon, Nonsense; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D052245:Usher Syndromes / Q000235:genetics* / Q000473:pathology
D001324:Autoantigens; D018797:Cell Cycle Proteins; C111329:CEP250 protein, human; D018389:Codon, Nonsense; D005136:Eye Proteins; C550125:PCARE protein, human
Cilia; Double homozygote; Usher syndrome