Comparative analysis of aryl-hydrocarbon receptor interacting protein-like 1 (Aipl1), a gene associated with inherited retinal disease in humans

Abstract

Mutations in AIPL1 cause Leber congenital amaurosis (LCA), the most severe form of inherited blindness in children; however, the function of this protein in normal vision remains unknown. To determine amino acid subsequences likely to be important for function, we have compared the protein sequence of several species. Sequence conservation is highest across the three Aipl1 tetratricopeptide (TPR) motifs and extends across the protein, except for a proline-rich amino acid sequence present only at the C-terminus of primate Aipl1. The length of the proline-rich region varies within primates; however, the length differences between human and primate Aipl1 do not correlate with evolutionary distance. These observations reinforce the importance of the TPR domains for function, the similarity of Aipl1 to a family of proteins that act as molecular chaperones, and the importance of comparative sequencing data for determination of whether AIPL1 sequence variants in patients are likely to cause retinopathy.

Fig. 1

(A) Protein sequence of Aipl1, indicating high degree of sequence conservation extending across the protein, outside of the proline-rich region present only at the C-terminus of primate Aipl1. Identical residues across all eight species are indicated with an asterisk. Residues with only conservative substitutions are indicated with a period. (B) Unrooted cladogram indicating the relationship of AIPL1 to the FK506-binding protein (FKBPs) and cyclophilin families of the human immunophilin proteins. Protein sequences used (GenBank number): cyclophilin A (P04374), cyclophilin B (P23284), cyclophilin C (NP_000934), cyclophilin 40 (BAA09923), FKBP12 (P20071), FKBP51 (Q13451), FKBP52 (Q02790), AIP (O00170), AIPL1 (AAF26708).