Ricerc@Sapienza

Zimmermann-Laband syndrome (ZLS) is a rare developmental disorder characterized by facial dysmorphism, gingival enlargement, nail aplasia or hypoplasia, hypertrichosis, and intellectual disability, with or without epilepsy. The genetic basis of ZLS has been recently reported by the identification of two disease genes by using a whole exome sequencing approach, KCNH1 and ATP6V1B2. ZLS has been proven as a genetic and phenotypic heterogeneous disease. Approximately 40% of ZLS cases do not carry mutations in the identified disease genes, KCNH1 and ATP6V1B2, indicating the existence of additional genes implicated in the pathogenesis. Preliminary functional studies on KCNH1 mutants demonstrated that mutations in KCNH1 perturb channel activity. However, to date, the functional role of KCNH1 in cells and in the pathogenesis of ZLS, is still incomplete. To gain insights into the molecular bases of ZLS, the applicant proposes studies with the aim of identify novel disease genes by using an exome sequencing strategy on a cohort of selected subjects with clinical features fitting ZLS, and of the characterization of their functional role of KCNH1 and molecular mechanisms of pathogenesis. Functional validation using in vitro approaches will be performed to study KCNH1 wild type and mutant protein subcellular localization, splicing variants, and the role in ciliogenesis.
Efforts aimed at disclosing molecular functions of KCNH1 and its dysfunctions in ZLS pathogenesis are a fundamental prerequisite that will provide molecular information with direct impact on diagnosis, prognosis, counselling and patient management.