Molecular bases of Zimmermann-Laband syndrome

Zimmermann-Laband syndrome (ZLS; MIM135500) is a rare developmental disorder characterized by facial dysmorphism, including coarsening of the face, bulbous soft nose, gingival enlargement, nail aplasia or hypoplasia, hypertrichosis, and intellectual disability, with or without epilepsy. To date, about 40 patients have been described with features fitting ZLS. With the aim of identifying ZLS causative gene/s a WES approach on three ZLS patients was performed and allowed us to identify two disease genes, KCNH1 and ATP6V1B2 (Kortum et al., 2015). An enlargement of the cohort was performed through the recruitment of further five patients, that were analyzed by WES or Sanger sequencing, disclosing the presence of additional mutations in KCNH1 and ATP6V1B2 genes (Kortum et al., 2015), and highlighting the role of potassium channels and vacuolar ATPase in the pathogenesis of this disease. KCNH1 gene encodes a member of the potassium channel, voltage-gated, subfamily H protein. Patch-clamp recordings on KCNH1 mutants identified in this work showed strong negative shifts in voltage-dependent activation, supporting a possible gain-of-function effect for all ZLSassociated KCNH1 mutants. ATP6V1B2 gene encodes the B2 subunit of the multimeric vacuolar H+ ATPase. Structural analysis predicts a perturbing effect of the mutation on complex assembly. Sanger sequencing screening of the coding sequence of the KCNH1 and ATP6V1B2 genes in four patients with clinical features within the ZLS clinical spectrum, disclosed the presence of mutation-negative patients, pointing to genetic heterogeneity for ZLS. To identify the “missing” ZLS disease genes, a WES approach on two KCNH1 and ATP6V1B2 mutation-negative subjects was performed, disclosing the presence of a novel likely pathogenic de novo variant in ATP6V1C1, encoding an interactor of ATP6V1B2. Common clinical features of patients mutated in KCNH1, ATP6V1B2 and ATP6V1C1 genes include craniofacial dysmorphism, gingival enlargement, mild to severe intellectual disability, and aplastic or hypoplastic nails and terminal phalanges, although with remarkable variability. Epilepsy is present only in KCNH1 mutated patients. A recruitment of additional ZLS and ZLS-related patients is ongoing; these subjects will be screened for mutations in previously and newly identified disease genes in order to provide a more accurate picture of the molecular spectrum of mutations and their associated clinical spectrum. Structural and functional studies are ongoing to characterize the effect of the ATP6V1B2 and ATP6V1C1 mutants on the proper assembly/activity of the ATPase complex.