Identification of isoforms of KALRN expressed in human brain and other key tissues using long read amplicon sequencing. Characterisation of isoforms of KALRN in adult human tissues

Kalirin (encoded by the KALRN gene) is a guanine nucleotide exchange factor (GEF) that facilitates the rapid activation of RAC/RHO GTPases, and is emerging as a key regulator of neural structural and functional plasticity. Kalirin signalling has been genetically and functionally linked to schizophrenia. The KALRN gene reportedly encodes three major, functionally distinct isoforms (Kal7, Kal9 and Kal12) via alternative splicing mechanisms. Kal7, reported to be the most abundant in brain, contains only a single RAC1-binding GEF domain, whilst Kal9 additionally contains a second GEF domain that binds RHOA (Remmers et al., 2014). However, KALRN splicing has to date largely been characterised in rat tissues. Our initial analyses suggest additional unannotated isoforms of human KALRN, with novel isoforms present in human brain. These may represent selective drug targets for psychiatric indications. The aim of this project is to identify the isoforms of KALRN expressed in human brain and other key tissues (particularly aorta), in order to identify lead kalirin target isoform(s) for schizophrenia.