Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis

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 GUCY2D (ref. 3), RPE65 (ref. 4) and CRX (ref. 5) are known to cause LCA, but one study identified disease-causing GUCY2D 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 D17S849 and D17S960-a region that excludes GUCY2D. The LCA in this family has been designated LCA4 (ref. 6). We describe here a new photoreceptor/pineal-expressed gene, AIPL1 (encoding aryl-hydrocarbon 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. AIPL1 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.

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

“…The following genes are known to be associated with LCA: GUCY2D, RPE65, SPATA7, AIPL1, LCA5, RPGRIP1, CRX, CRB1, CEP290, IMPDH1, RD3, RDH12, KCNJ13, LRAT and TULP1. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] It is difficult to estimate the proportion of patients with mutations in the different genes, as some, such as IMPDH1 (LCA11) is considered to be rare, other, as CEP290 accounts for almost 20%, and for some such as TULP1 and LRAT the number is uncertain. One of the most studied LCA genes is CRB1 at 1q31q32.1, which consists of 12 exons and encodes a protein Crumbs homologue that participates in determination and maintenance of photoreceptor architecture.…”

Mutations in LCA5 are an uncommon cause of Leber congenital amaurosis (LCA) type II

“…60%) [Perrault et al, 1999;Hanein et al, 2004]. Up to date, 13 LCA genes have been mapped, 10 of which have been identified: GUCY2D/retGC1 [Perrault et al, 1996], RPE65 [Marlhens et al, 1997], CRX [Swaroop et al, 1999], AIPL1 [Sohocki et al, 2000], RPGRIP1 [Dryja et al, 2001;Gerber et al, 2001], CRB1 [den Hollander et al, 2001;Gerber et al, 2002], LRAT [Thompson and Gal, 2003], TULP1 , RDH12 [Janecke et al, 2004;Perrault et al, 2004], CEP290 [den Hollander et al, 2006;Perrault et al, 2007]. Mutations in 3/10of them were shown to account for LCA type I (GUCY2D, RPGRIP1, CEP290) while, although less frequent, LCA type II was hitherto accounted for by mutations in 7/10 genes (RPE65, CRX, AIPL1, CRB1, LRAT TULP12, RDH12) [Perrault et al, 1999;Hanein et al, 2004;Perrault et al, 2004;Perrault et al, 2007].…”

Genetic disorders involving molecular-chaperone genes: A perspective

“…82,83 A number of loci and mutated genes have been implicated in LCA. 83,84 One of these genes, AIPL1 (aryl-hydrocarbon receptor-interacting protein-like 1), is involved in LCA4.…”

“…82,86,87 Comparative analyses of primary structures revealed that all mammalian AIPs are conserved and are related to the FKBP group of chaperones. 85 The FKBP chaperones function in steroid receptor signaling, heat-shock response, and immunosuppression.…”