Mutations in a new photoreceptor-pineal gene on 17p cause leber congenital amaurosis. Nat gen 2000;24:79-83.

Abstract

Leber congenital amaurosis (LCA, MIM 204000) accounts for at least 5% of all inherited retinal disease and is the most severe inherited retinopathy with the earliest age of onset. Individuals affected with LCA are diagnosed at birth or in the first few months of life with severely impaired vision or blindness, nystagmus and an abnormal or flat electroretinogram (ERG). Mutations in <i>GUCY2D</i> (ref. 3), <i>RPE65</i> (ref. 4) and <i>CRX</i> (ref. 5) are known to cause LCA, but one study identified disease-causing <i>GUCY2D</i> mutations in only 8 of 15 families whose LCA locus maps to 17p13.1 (ref. 3), suggesting another LCA locus might be located on 17p13.1. Confirming this prediction, the LCA in one Pakistani family mapped to 17p13.1, between <i>D17S849</i> and <i>D17S960</i>—a region that excludes <i>GUCY2D</i>. The LCA in this family has been designated LCA4 (ref. 6). We describe here a new photoreceptor/pineal-expressed gene, <i>AIPL1</i> (encoding arylhydrocarbon interacting protein-like 1), that maps within the LCA4 candidate region and whose protein contains three tetratricopeptide (TPR) motifs, consistent with nuclear transport or chaperone activity. A homozygous nonsense mutation at codon 278 is present in all affected members of the original LCA4 family. <i>AIPL1</i> mutations may cause approximately 20% of recessive LCA, as disease-causing mutations were identified in 3 of 14 LCA families not tested previously for linkage.