Phenotypic Analyses of Leber Congenital Amaurosis Patients Caused by LCA5 Mutations

Abstract

Purpose: : LCA5 encodes lebercilin and is expressed ubiquitously during development, with increased expression at adult stages in ciliated tissues like photoreceptors and olfactory neurons. Lebercilin is an integral part of the emerging "lebercilin interactome" at the basal body and connecting cilium of photoreceptors. Another member, the centrosomal ninein-like protein Nlp, was recently shown to mechanistically link Usher syndrome and Leber congenital amaurosis (LCA). Our purpose was to determine the LCA5 mutation spectrum and frequency in a large cohort of LCA and RP patients and to evaluate the ocular and olfactory phenotypes of genotyped LCA5 patients.

Methods: : Nine exons and intron-exon boundaries of LCA5 were sequenced in 306 LCA and 94 RP patients. LCA patients with previously found LCA5 nullmutations were phenotyped by ERG measures, ETDRS acuities, and Goldmann visual fields. LCA patients and their heterozygous carrier parents were evaluated by UPSIT (Sensonics Inc) olfactory testing. Responses to the 40 item forced answer tests were compared to normal controls.

Results: : We found the following variants in LCA: Asn113Ser, Arg301His, Thr97Ala and His61Tyr. We found a Arg183Gln variant in RP. We excluded all variants from 94 normals, but we assume that all are non-pathogenic. Three previously genotyped LCA5 patients (one with a homozygous p. Pro493ThrfsX1 frameshift mutation and two with a homozygous deletion of 1598 bp; g. -19612_-18015del) were found to have significant improvements in visual function. Improvements were from no fixation at birth, to 20/400 at age 10 and 20/100 at age 20 years. Affected individuals and heterozygous carriers had significant olfactory dysfunction (p<0.01), unknown to themselves.

Conclusions: : LCA5 mutations are a rare cause of LCA and do not appear to associate with RP. Olfactory dysfunction and visual improvement in a patient with LCA may be indicative for mutations in LCA5. Olfactory dysfunction in patients with LCA5 mutations is similar to those with CEP290 mutations and may suggest a systemic ciliopathy. Visual improvements in patients with LCA5 mutations are similar to those found in patients with CRX mutations. These findings warrant caution in interpreting outcomes in upcoming treatment trials. We hypothesize that protein redundancy in the lebercilin interactome may explain the significant improvements in visual function.

Keywords: retinal degenerations: hereditary • genetics • visual development: infancy and childhood