Fortschritte in der Gentechnik
Offener Zugang

Abstrakt

Altered signal transduction and cellular permeability in retinal bipolar cells caused by mutated TRPM1 and MYO7A could reveal new insights of retinal degeneration pathways

Luigi Donato

The earliest step of the visual processing is the generation of parallelinformation channels responding to increases versus decreasesin light intensity. Such ON and OFF responses begin at thefirst retinal synapse where two classes of postsynaptic bipolar cellsreact with opposite polarities to glutamate released by photoreceptors.While dendrites of OFF-bipolar cells contain ionotropicglutamate receptors of the AMPA/kainite class, the ON-bipolarcell dendrites express a unique metabotropic glutamate receptor6 (mGluR6). TRPM1 is a component of the transduction cationchannel negatively regulated by the mGluR6 cascade in ON bipolarcells, and forms a macromolecular complex with other proteinsincluding the just cited mGluR6, GPR179, nyctalopin, and theregulator of G protein signaling proteins. Mutations of humanTRPM1 are associated with hereditary and acquired diseases inwhich the retinal ON pathway is selectively affected, such as congenitalstationary night blindness. It represents a clinically and geneticallyheterogeneous group of retinal disorders, whose affectedpatients lack rod function and suffer from night blindness startingin early childhood. We present data coming from whole exomesequencing of a family in which 2 sons were diagnosed for an orphanform of retinal dystrophy, even if characterized by two differentphenotypes. Both patients presented a causative mutation ofUsher Syndrome in MYO7A gene, but only one showed a causativemutation of CSNB in TRPM1 gene (c.470C>T, Ser157Phe).We evaluated possible consequences of identified variants on eachcorresponding protein, analyzing their possible interaction and biologicalprocesses that their alterations could impair.