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, Fgf9Y162C 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 Fgf9Y162C mutants in a virtual drum indicated a gene-dosage dependent vision loss of almost 50%. The smaller lenses in Fgf9Y162C suggested a role of Fgf9 during lens development. Histological investigations showed that lens growth retardation starts during embryogenesis and continues after birth. Young Fgf9Y162C lenses remained transparent but developed age-related cataracts. Taken together, Fgf9Y162C 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.
Highlights
According to the World Health Organization, 315 million people are visually impaired worldwide. 43 million of them suffer from complete blindness (,3/60 presenting visual acuity), leading to a significant loss of life quality and shortened life time
Microphakia is characterized by smaller lenses and usually occurs together with other systemic abnormalities inside and outside the eye as part of the Warburg Micro syndrome (WARBM1; MIM #600118), Marfan’s syndrome (MFS; MIM #154700), or rhizomelic chondrodysplasia calcificans punctata (RCDP; MIM #215100) [2,3,4]
The 855 ARG transition is predicted to cause an exchange of Tyr to Cys at amino acid position 162 of the Fgf9 protein
Summary
According to the World Health Organization, 315 million people are visually impaired worldwide. 43 million of them suffer from complete blindness (,3/60 presenting visual acuity), leading to a significant loss of life quality and shortened life time. Microphakia is characterized by smaller lenses and usually occurs together with other systemic abnormalities inside and outside the eye as part of the Warburg Micro syndrome (WARBM1; MIM #600118), Marfan’s syndrome (MFS; MIM #154700), or rhizomelic chondrodysplasia calcificans punctata (RCDP; MIM #215100) [2,3,4]. These syndromes are initiated by mutations in RAB3GAP (WARMB1; MIM *602536), FBN1 (MFS; MIM *134797), and PEX7 (RCDP; MIM +601757), respectively [5,6,7,8,9]. Negative effects on lens polarity could be initiated by lens-specific over-expression of Fg f1 (MGI: 95515), Fg f3 (MGI: 95517), Fg f4
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