Potential involvement of more than one locus in trait manifestation for individuals with Leber congenital amaurosis

Abstract

Leber congenital amaurosis (LCA) is a clinically and genetically heterogeneous retinal dystrophy. The causes of LCA have been unraveled partially at the molecular level. At least 14 genes have been reported that, when mutated, result in LCA. To understand the roles of the known genes in LCA, a group of outbred subjects from 60 apparently either recessive families, with one or more affected individuals, or isolated patients were evaluated. One affected individual from each family underwent comprehensive mutational analysis by direct DNA sequencing of all coding regions and splice junctions of 13 LCA genes. Mutations were identified in 70% of individuals. CEP290 made the largest contribution to the identified mutations, providing 43% of those mutant alleles. We identified seven families in which affected individuals with two mutant alleles, sufficient to cause disease, had an additional mutation at a second LCA locus. Our findings suggest that mutational load can be important to penetrance of the LCA phenotype.

Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis

“…A recent selective screen of 13 LCA genes in 60 affected subjects revealed a striking 43% of the mutant alleles in Cep290 (24), suggesting a significant contribution of this gene to retinal disease manifestation. In addition, mutations in Cep290 produce varying clinical outcomes of JBTS (25)(26)(27), MKS (28)(29)(30), and BBS (31).…”

Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

“…The occurrence of variants in multiple LCA genes has previously been reported. 12,37 So far, it is unclear whether they influence disease penetrance or represent modifying alleles. Undoubtedly, application of MPS-based strategies on a large scale will reveal more insights into the understanding of intra-and interfamilial variability, individual phenotypes, and a patient's visual prognosis.…”

A “so cilia” network: cilia proteins start “social” networking

“…This clinically and genetically heterogenous disease is caused by mutations in at least 16 genes (Table 1), with mutations in the CEP290 gene being the most common cause of LCA. Mutations in CEP290 can also cause other ciliopathies, including Joubert syndrome, Meckel-Gruber syndrome, and BBS (6). While extending their previous work on LCA (7), Rachel et al (3) found that almost 10% of individuals with LCA have a mutation in MKKS, a gene also found mutated in individuals with MKKS and BBS.…”

“…Specifically, activation of the ATR/Chk1 pathway during replication stress both prevents collapse of troubled replication forks into DNA double-strand breaks and inhibits cell-cycle progression into M phase. Previous culture-based studies have demonstrated that suppressing the G 2 -M phase checkpoint through ATR and Chk1 inhibition is particularly toxic when combined with loss of G 1 -S checkpoint function via p53 deficiency (4)(5)(6)(7)(8)(9). This dual loss produces a checkpoint short circuit ( Figure 1A).…”

“…Indeed, it was recently reported that both mitochondrial and ER stress induce Parkin expression and that Parkin counteracts the stress in both organelles, thereby preventing neuronal death (17). The new evidence generated by Selvaraj et al (6) indicating involvement of impaired SOCE in a mitochondrial toxin-based model of PD suggests potential new therapeutic approaches aimed at halting the neurodegenerative process in PD. These include activation or upregulation of TRPC1 channels, enhancement of ER Ca 2+ uptake, and tweaking of the UPR.…”