Dominant LMAN2L mutation causes intellectual disability with remitting epilepsy

Alkhater, Reem A.; Wang, Peixiang; Ruggieri, Alessandra; Israelian, Lori; Walker, Susan; Scherer, Stephen W.; Smith, Mary Lou; Minassian, Berge A.

The mutation in the present cases relocates at least a portion of LMAN2L to an aberrant cell membrane location, similar to the effect of experimental manipulations of the protein's ER retention signal. 7, 8 The precise effect on glycoprotein chaperoning remains unknown. The previous mutation being recessively inherited suggests that the present one might operate through a possible dominant-negative mechanism. Alternatively, it is merely happloinsufficient to an extent equivalent to the partial biallelic deficiency of the first mutation. That both mutations are not full loss-of-function suggests that only mutations with particular effects or partial loss of function permit viability. Which brain glycoproteins are processed by LMAN2L is unknown and may include neurotrophins or other secreted glycoproteins involved in neurodevelopment. It may also include secreted glycoproteins associated with epilepsy, for example reelin and LGI1, mutations and non-secretion of which cause lateral temporal lobe epilepsy. 9 Finally, it may include Lgi2, a secreted glycoprotein related to LGI1, mutation, and nonsecretion of which in dogs result in a remitting epilepsy. 10 The neurological syndrome associated with LMAN2L mutation as described in this study and the original report opens a new avenue toward understanding the roles and processing of secreted glycoproteins in brain development and function relevant to epilepsy (including epilepsy remission), intellectual development, and possibly ADHD, bipolar disorder, and schizophrenia.