Leber congenital amaurosis is a severe retinal dystrophy, causing blindness or severe visual impairment at birth or during the first months of life. It is generally inherited in an autosomal recessive manner and is genetically heterogeneous. A consanguineous ... Leber congenital amaurosis is a severe retinal dystrophy, causing blindness or severe visual impairment at birth or during the first months of life. It is generally inherited in an autosomal recessive manner and is genetically heterogeneous. A consanguineous French Canadian family with 4 sibs affected by LCA was ascertained by den Hollander et al. (2006). Affected individuals were all blind or severely visually impaired at birth. Two of the 4 sibs experienced seizures and had no other neurologic symptoms. All 4 affected sibs had normal cognitive function. Detailed CT scanning revealed no molar-tooth sign, no cerebellar atrophy, and no structural signs of Joubert syndrome (213300). McEwen et al. (2007) found that affected individuals from the family reported by den Hollander et al. (2006) had severely impaired olfactory function, whereas heterozygous mutation carriers had mild to severe microsmia. They noted that all patients queried before testing reported self-assumed normal olfactory functioning. They postulated that olfactory dysfunction may be prevalent in patients with ciliary diseases. Using in vivo microscopy of the central retina and colocalized rod and cone vision, Cideciyan et al. (2007) found that patients with LCA10 due to mutations in the CEP290 gene retained photoreceptor and inner laminar architecture in the cone-rich central retina, independent of severity of visual loss. Surrounding the cone-rich island was photoreceptor loss and distorted retina, suggesting neural-glial remodeling. Foveal cones were preserved, and visual brain pathways were anatomically intact. Despite severe blindness and rapid rod cell death, the findings suggested an opportunity for visual restoration of central vision. Papon et al. (2010) studied the otorhinolaryngologic phenotype and examined nasal cilia of 7 LCA patients from 6 families with known CEP290 mutations. In 5 of 7 cases, electron microscopy could be performed, which revealed high levels of respiratory cilia defects, involving the dynein arms, central complex, and/or peripheral microtubules. All patients had rarefaction of ciliated cells and a variable proportion of short cilia. Frequent but moderate and heterogeneous clinical and ciliary beating abnormalities were found. CEP290 was highly expressed in neural retina and nasal epithelial cells compared to other tissues. Papon et al. (2010) suggested that the presence of respiratory symptoms in LCA patients might represent additional clinical criteria for CEP290 genotyping.
Because of the function of the CEP290 gene and the phenotype of the rd16 mice, den Hollander et al. (2006) considered CEP290 to be an excellent candidate gene for LCA10 in the French Canadian family. They sequenced all ... Because of the function of the CEP290 gene and the phenotype of the rd16 mice, den Hollander et al. (2006) considered CEP290 to be an excellent candidate gene for LCA10 in the French Canadian family. They sequenced all 53 coding exons and splice junctions and detected only 1 synonymous sequence variant in exon 21 that was not a known SNP. Since the variant was located between the splice donor site and a predicted exonic splice enhancer, den Hollander et al. (2006) reasoned that it may have an effect on the splicing of this exon. However, this could not be confirmed. Subsequent analysis of the complete CEP290 mRNA by RT-PCR revealed an aberrant splice product with insertion of a 128-bp cryptic exon between exons 26 and 27, which introduced a stop codon immediately downstream of exon 26. Sequencing of the genomic DNA surrounding the cryptic exon showed an A-to-G transition 5 bp downstream of the cryptic exon (2991+1655A-G; 610142.0005). The mutation created a strong splice donor site, which presumably led to efficient splicing of the cryptic exon into the CEP290 mRNA. To determine whether this mutation could be a common cause of LCA10, den Hollander et al. (2006) screened 76 unrelated patients with LCA for the 2991+1655A-G mutation by allele-specific PCR. Four patients were found to be homozygous for the mutation, and 12 were heterozygous. The mutation was not detected in 223 French Canadian controls, and only 1 of 248 Dutch control individuals was found to be heterozygous for the mutation. Den Hollander et al. (2006) suggested that this mutation may account for up to 21% of LCA cases. Twelve patients who were heterozygous for 2991+1655A-G were analyzed for additional mutations in the 53 coding exons and splice junction of CEP290 by heteroduplex analysis and/or direct sequencing. In all patients, they detected a heterozygous mutation on the other allele. In 9 LCA families in which 2 CEP290 mutations were identified by den Hollander et al. (2006), family members were available for segregation analysis. In all 9 families, segregation of the variants as expected for autosomal recessive inheritance was observed. The patients had no neurologic symptoms typical of Joubert syndrome, had normal cognitive function, and showed no clinical signs of renal disease. The patients studied by den Hollander et al. (2006) originated from various geographic regions, including Canada, Germany, the Netherlands, and Italy. The results suggested a complete loss of function of both CEP290 alleles leads to Joubert syndrome, whereas patients with LCA10 have a small amount of residual CEP290 activity. In a patient with LCA10, Cideciyan et al. (2007) identified compound heterozygosity for 2 mutations in the CEP290 gene: the common splice site defect (610142.0005) and a 5-bp deletion (1260delTAAAG; 610142.0011).