A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype.
PURPOSE. To identify the genetic defect in a family with variable retinal phenotypes. The proband had a diagnosis of Leber congenital amaurosis (LCA), whereas her two cousins had an early-onset severe retinal dystrophy (EOSRD) with useful vision. A distant family member had retinitis pigmentosa (RP). METHODS. DNA samples of the affected family members were genotyped with 250 K genome-wide SNP microarrays. Genetic defects were localized by linkage analysis and homozygosity mapping, and candidate genes were analyzed by sequencing. Patients underwent a full ophthalmic examination. RESULTS. Compound heterozygous mutations in CEP290 were identified in the proband and her two cousins: the frequent c.2991+1655A>G founder mutation and a novel nonsense mutation in exon 7 (c.451C>T, p.Arg151X). The proband had nystagmus, hyperopia, a flat electroretinogram (ERG), and decreased visual acuity (20/250) from birth. The two cousins had minimal scotopic ERG responses at the age of 2. In one of these patients, visual acuity had reached a level of 20/32 at age 5, which is high for patients with CEP290 mutations. Analysis of the CEP290 mRNA in affected individuals revealed altered splice forms in which either exon 7 or exons 7 and 8 were skipped. In both mutant cDNA products, the open reading frame was not disrupted. Furthermore, homozygosity mapping and mutation analysis in the distant family member affected by RP revealed a homozygous mutation in MERTK, but no CEP290 mutations. This MERTK mutation was heterozygously present in the most severely affected (LCA) patient, but was absent in the two more mildly affected cousins. CONCLUSIONS. A novel nonsense mutation in CEP290 results in nonsense-associated altered splicing. That the remaining open reading frame is intact may explain the less severe phenotype observed in the two affected cousins. The additional heterozygous mutation in MERTK may clarify the more severe phenotype in the proband. This study extends the phenotypic spectrum of CEP290-associated diseases at the mild end.
Rotterdam Eye Hospital, Rotterdam, The Netherlands.
Karin W
KW
Littink
Jan-Willem R
JW
Pott
Rob W J
RW
Collin
Hester Y
HY
Kroes
Joke B G M
JB
Verheij
Ellen A W
EA
Blokland
Marta
M
de Castro Miró
Carel B
CB
Hoyng
Caroline C W
CC
Klaver
Robert K
RK
Koenekoop
Klaus
K
Rohrschneider
Frans P M
FP
Cremers
L Ingeborgh
LI
van den Born
Anneke I
AI
den Hollander
D000951:Antigens, Neoplasm / Q000235:genetics*; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002648:Child; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005091:Exons / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D009759:Nystagmus, Pathologic / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D012162:Retinal Degeneration / Q000235:genetics*; D014792:Visual Acuity; D000076202:c-Mer Tyrosine Kinase
D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase