Given the very close proximity of the risk SNPs to the transcriptional start site of RPGRIP1L (human ortholog of mouse Ftm), which is adjacent to and coded for on the opposite DNA strand to FTO,28 it was reasonable to query the possible role of RPGRIP1L in the control of body-weight. There were two main reasons why the focus of study began with FTO and not RPGRIP1L. Firstly, while FTO was found to be nutritionally regulated within the hypothalamus,140 this was not true for RPGRIP1L, which is known to localize in the primary cilia and centrosomes of ciliated cells. Secondly, human defects in RPGRIP1L exist and cause Joubert syndrome type 7 (JBTS), which presents clinically with cerebellar and brainstem malformation and renal failure.160 The patients do not present with any obvious body weight-related phenotypes, with the caveat that any potential ‘lean’ phenotype is difficult to ascertain in a healthy individual, let alone someone who is severely ill. Deletion of the mouse ortholog Rpgrip1l (Ftm) recapitulates the cerebral, renal and hepatic defects seen in Joubert’s patients.160
