Two different retinal dystrophies accounted for by different CRB1 mutations in a single nuclear family.

Abstract

Abstract: : Purpose: To identify the molecular bases of the occurrence of late onset retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) in a single small nuclear family. Methods: The family of interest is shown on the enclosed figure. The diagnosis of Leber congenital amaurosis was unambiguous in individual III–3. In the first months of life he was found to carry typical signs of the disease ie absence of ocular pursuit, searching nystagmus, oculo–digital signs of Franceschetti and non recordable ERG. At birth, his parents (II3 and II4) were considered healthy. Three years later, an ophthalmologic examination of the father (II3), requested by a company doctor, detected a moderate visual loss. Complete explorations of this 38 year old man revealed typical retinitis pigmentosa. The screening of the seven already known LCA genes was first undertaken in the LCA patient III3 using DHPLC and direct sequencing and then extended to the whole family. Results: Patient III3 was found to be compound heterozygote for two CRB1 mutations (p.L1107P/p.S1025I). Segregation analysis showed that each of the two mutations was inherited from one parent. The discovery of RP in II3 prompted us to screen the whole CRB1 sequence. Indeed, two other non conservative amino–acid changes were identified in this RP patient (V1325F, A1328V). Subsequently, the segregation analysis performed in the entire family showed that II3 carried two mutant CRB1 alleles: L1107P, inherited from the healthy grand–mother I2 and transmitted to the LCA patient III3, and a complex mutant allele [V1235F and A1328V] inherited from the healthy grand father I1. Conclusions: This observation emphasises that CRB1 mutations can be responsible for late–onset RP or LCA depending on the association of disease alleles in the patient. Considering that the patients in the reported family shared 50% of their genetic background, one can reasonably speculate that genotype–phenotype correlations may exist for the CRB1 gene.  

Keywords: retinal degenerations: hereditary • gene screening • genetics