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.

Lectin mannose-binding (LMAN) is a family of three ubiquitously expressed proteins (LMAN1, LMAN2, and LMAN2L), which, anchored in the endoplasmic reticulum (ER) through a C-terminal KRFY sequence interact with glucan chains of select glycoproteins to direct them to extracellular secretion. LMAN1 (ERGIC-53), the best-studied of the group, is so far known to guide five endogenous glycoproteins (Factors V and VIII, Cathepsins C and Z, and a1-antitrypsin) and glycoproteins of five infecting viruses. Complete loss of LMAN1 in humans results in a bleeding disorder and viral resistance, but not a neurological phenotype, indicating that its nervous system function is nonessential. 1 LMAN2 likewise has not been associated with neurological disease. LMAN2L is the least studied of the three; the glycoproteins it processes for secretion are unknown. First evidence that LMAN2L may have a role in brain glycoprotein handling came when genome-wide association studies showed significant association between a polymorphism in LMAN2L and attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, and schizophrenia. 2,3 Subsequently, a recessively inherited variant, p.R53Q, was found to segregate in affected members of a seven-affected multiplex family with nondysmorphic intellectual disability and remitting epilepsy. The causal nature of this variant was further supported by strong in silico evidence, reviewed below. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.