title: The pathologic effect of a novel neomorphic Fgf9(Y162C) allele is restricted to decreased vision and retarded lens growth.
abstract: Fibroblast growth factor (Fgf) signalling plays a crucial role in many developmental processes. Among the Fgf pathway ligands, Fgf9 (UniProt: P54130) has been demonstrated to participate in maturation of various organs and tissues including skeleton, testes, lung, heart, and eye. Here we establish a novel Fgf9 allele, discovered in a dominant N-ethyl-N-nitrosourea (ENU) screen for eye-size abnormalities using the optical low coherence interferometry technique. The underlying mouse mutant line Aca12 was originally identified because of its significantly reduced lens thickness. Linkage studies located Aca12 to chromosome 14 within a 3.6 Mb spanning interval containing the positional candidate genes Fgf9 (MGI: 104723), Gja3 (MGI: 95714), and Ift88 (MGI: 98715). While no sequence differences were found in Gja3 and Ift88, we identified an A→G missense mutation at cDNA position 770 of the Fgf9 gene leading to an Y162C amino acid exchange. In contrast to previously described Fgf9 mutants, Fgf9(Y162C) carriers were fully viable and did not reveal reduced body-size, male-to-female sexual reversal or skeletal malformations. The histological analysis of the retina as well as its basic functional characterization by electroretinography (ERG) did not show any abnormality. However, the analysis of head-tracking response of the Fgf9(Y162C) mutants in a virtual drum indicated a gene-dosage dependent vision loss of almost 50%. The smaller lenses in Fgf9(Y162C) suggested a role of Fgf9 during lens development. Histological investigations showed that lens growth retardation starts during embryogenesis and continues after birth. Young Fgf9(Y162C) lenses remained transparent but developed age-related cataracts. Taken together, Fgf9(Y162C) is a novel neomorphic allele that initiates microphakia and reduced vision without effects on organs and tissues outside the eye. Our data point to a role of Fgf9 signalling in primary and secondary lens fiber cell growth. The results underline the importance of allelic series to fully understand multiple functions of a gene.
authors.affiliation: German Research Center for Environmental Health, Institute of Developmental Genetics, Neuherberg, Germany. oliver.puk@helmholtz-muenchen.de
authors.forename: Oliver
authors.initials: O
authors.lastname: Puk
authors.forename: Gabriele
authors.initials: G
authors.lastname: Möller
authors.forename: Arie
authors.initials: A
authors.lastname: Geerlof
authors.forename: Kathrin
authors.initials: K
authors.lastname: Krowiorz
authors.forename: Nafees
authors.initials: N
authors.lastname: Ahmad
authors.forename: Sibylle
authors.initials: S
authors.lastname: Wagner
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Jochen
authors.initials: J
authors.lastname: Graw
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D002386:Cataract / Q000235:genetics; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006239:Haplotypes; D006493:Heparin / Q000378:metabolism; D007908:Lens, Crystalline / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014785:Vision, Ocular / Q000235:genetics*; D014792:Visual Acuity / Q000235:genetics
chemical_list: D051525:Fibroblast Growth Factor 9; D006493:Heparin